Compounds and methods for modulating cerebral amyloid angiopathy

ABSTRACT

The invention provides methods of inhibiting cerebral amyloid angiopathy. The invention further provides methods of treating a disease state characterized by cerebral amyloid angiopathy in a subject.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/747,408, filed Dec. 22, 2000, which claims the benefit of priorityunder 35 U.S.C. 119(e) to copending U.S. Provisional Application No.60/171,877, filed Dec. 23, 1999, the entire contents of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Cerebral amyloid angiopathy (CAA) remains a largely untreatable diseaseoften not diagnosed until autopsy. It ranges in severity fromasymptomatic amyloid deposition in otherwise normal cerebral vessels tocomplete replacement and breakdown of the cerebrovascular wall. SevereCAA can cause lobar cerebral hemorrhage, transient neurologic symptoms,and dementia with leukoencephalopathy. (see Greenberg, Neurology 1998,51:690-694).

Amyloid-β (Aβ) is a toxic peptide which is implicated in thepathogenesis of CAA. Aβ peptide is derived from a normal proteolyticcleavage of the precursor protein, the Amyloid-β precursor protein(βAPP). Advanced cases of CAA demonstrate structural changes to thewalls of the amyloid-laden vessel such as cracking between layers,smooth muscle cell toxicity, microaneuryism formation, and fibrinoidnecrosis.

The exact mechanisms involved in the genesis of cerebral amyloidangiopathy (CAA) have not been completely established, but it appearsthat a preponderance of the form of the 39-40 amino acid Aβ peptide(Aβ40) is responsible for the deposits on blood vessel wall cells whichlead to CAA, in comparison to the 42-43 amino acid Aβ peptides (Aβ42 andAβ43), which are implicated in other amyloid-related conditions such asAlzheimer's Disease (AD).

SUMMARY OF THE INVENTION

The present invention provides methods for modulating, e.g., inhibitingand/or preventing, cerebral amyloid angiopathy. The present invention isbased, at least in part, on the discovery that compounds which interferewith the deposition of Aβ peptide, e.g., the Aβ40 peptide, in bloodvessel wall cells, prevent the structural changes to cerebral bloodvessels like capillaries, that lead to CAA. It is believed, withoutintending to limit the invention as claimed herein, that the compoundsof the invention interfere with the association of the Aβ40 peptide,e.g., the association of the Aβ40 peptide to the sulfate GAGs present atthe smooth muscle cell surface, and thus prevent intracellular andextracellular amyloid deposition. However, while it is believed thatinhibition of Aβ40 is a significant factor in inhibiting CAA, the Aβ40inhibitors of the invention may well work in other ways to inhibit orprevent CAA, and these are intended to be part of the present invention.

Accordingly, this invention pertains to a method of modulating, e.g.,inhibiting and/or preventing, cerebral amyloid angiopathy. The methodincludes contacting a blood vessel wall cell with an Aβ40 inhibitor,such that the compound inhibits or prevents cerebral amyloid angiopathy.The Aβ40 inhibitor is believed to at least interfere with the ability ofthe Aβ40 peptide to form amyloid fibrils and/or with the ability of theAβ40 peptide to bind to a cell (e.g., blood vessel wall smooth musclecells, pericytes or endothelial cells) surface molecule or structure,forming deposits on the walls of the blood vessel and thus preventAβ-induced cell death and/or the structural changes to cerebral bloodvessels, e.g., capillaries, medium sized arteries, or arterioles, thatlead to CAA. The Aβ40 peptide can be either in a soluble form or in afibril form.

In one embodiment, the Aβ40 inhibitor may be ethanesulfonic acid,1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonicacid, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid,2-aminoethanesulfonic acid, or 4-hydroxy-1-butanesulfonic acid, andpharmaceutically acceptable salts thereof. In other preferredembodiments, the Aβ40 inhibitor may be 1-butanesulfonic acid,1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid,or 4-heptanesulfonic acid, and pharmaceutically acceptable saltsthereof. In yet further preferred embodiments, the Aβ40 inhibitor may be1,7-dihydroxy-4-heptanesulfonic acid, 3-amino-1-propanesulfonic acid, ora pharmaceutically acceptable salt thereof. In another embodiment theAβ40 inhibitor is a peptide or a peptidomimetic which interacts withspecific regions of the Aβ peptide such as the regions responsible forcellular adherence (aa 10-16), GAG binding site region (13-16) or theregion responsible for the β-sheet formation (16-21). These peptides arethe d-stereoisomers of the Aβ or complementary image of the Aβ peptide.

In one embodiment, the Aβ40 inhibitor is administered in apharmaceutically acceptable formulation. The pharmaceutically acceptableformulation can be a dispersion system like a lipid-based formulation, aliposome formulation, or a multivesicular liposome formulation. Thepharmaceutically acceptable formulation can also comprise a polymericmatrix, e.g., synthetic polymers such as polyesters (PLA, PLGA),polyethylene glycol, poloxomers, polyanhydrides, and pluronics; ornaturally derived polymers, such as albumin, alginate, cellulosederivatives, collagen, fibrin, gelatin, and polysaccharides. In otherpreferred embodiments, the pharmaceutically acceptable formulationprovides sustained delivery of the Aβ40 inhibitor to the target site.

Yet another aspect of the invention pertains to a method of treating adisease state characterized by cerebral amyloid angiopathy in a subject.The method includes administering an Aβ40 inhibitor to the subject, suchthat the disease state characterized by cerebral amyloid angiopathy istreated, e.g., inhibited or prevented.

Another aspect of the invention pertains to a method of modulating,e.g., inhibiting and/or preventing, cerebral amyloid angiopathy,including contacting a blood vessel wall cell with an Aβ40 inhibitorhaving the structure:

Q-[—Y⁻X⁺]_(n)

wherein Y⁻ is an anionic group at physiological pH; Q is a carriergroup; X⁺ is a cationic group; and n is an integer selected such thatthe biodistribution of the Aβ40 inhibitor for an intended target site isnot prevented while maintaining activity of the Aβ40 inhibitor, providedthat the Aβ40 inhibitor is not chondroitin sulfate A, such that cerebralamyloid angiopathy is inhibited or prevented.

In yet another aspect, the invention features a method of modulating,e.g., inhibiting and/or preventing, cerebral amyloid angiopathy,including contacting a blood vessel wall cell with an Aβ40 inhibitorhaving the structure:

wherein Z is XR² or R⁴, R¹ and R² are each independently hydrogen, asubstituted or unsubstituted aliphatic group (preferably a branched orstraight-chain aliphatic moiety having from 1 to 24 carbon atoms in thechain; or an unsubstituted or substituted cyclic aliphatic moiety havingfrom 4 to 7 carbon atoms in the aliphatic ring; preferred aliphatic andcyclic aliphatic groups are alkyl groups, more preferably lower alkyl),an aryl group, a heterocyclic group, or a salt-forming cation; R³ ishydrogen, lower alkyl, aryl, or a salt-forming cation; R⁴ is hydrogen,lower alkyl, aryl or amino (including alkylamino, dialkylamino(including cyclic amino moieties), arylamino, diarylamino, andalkylarylamino); X is, independently for each occurrence, O or S; Y¹ andY² are each independently hydrogen, halogen (e.g., F, Cl, Br, or I),alkyl (preferably lower alkyl), amino, hydroxy, alkoxy, or aryloxy; andn is an integer from 0 to 12 (more preferably 0 to 6, more preferably 0or 1), such that cerebral amyloid angiopathy is inhibited or prevented.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, at least in part, on the discovery thatcompounds which interfere with the ability of the Aβ40 peptide to formdeposits in cerebral blood vessels, e.g., on the smooth muscle cellsthereof, and thus prevent the structural changes to cerebral bloodvessels that lead to CAA.

As used herein, the language “contacting” is intended to include both invivo, in vitro, or ex vivo methods of bringing an Aβ40 inhibitor intoproximity with a blood vessel wall cell, such that the Aβ40 inhibitorcan inhibit or prevent CAA, e.g., via inhibiting the deposition of theAβ40 peptide. For example, the blood vessel wall cell can be contactedwith an Aβ40 inhibitor in vivo by administering the Aβ40 inhibitor to asubject either parenterally, e.g., intravenously, intradermally,subcutaneously, orally (e.g., via inhalation), transdermally(topically), transmucosally, or rectally. A blood vessel wall cell canalso be contacted in vitro by, for example, adding an Aβ40 inhibitorinto a tissue culture dish in which blood vessel wall smooth musclecells are grown.

As used herein, the term “subject” is intended to include animalssusceptible to states characterized by cerebral amyloid angiopathy,preferably mammals, most preferably humans. In a preferred embodiment,the subject is a primate. In an even more preferred embodiment, theprimate is a human. Other examples of subjects include experimentalanimals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.The experimental animal can be an animal model for a disorder, e.g., atransgenic mouse.

The term “blood vessel wall cell” includes smooth muscle cells,pericytes and endothelial cells. In a preferred embodiment the bloodvessel wall cell is a smooth muscle cell.

Aβ40 Inhibitors

In one embodiment, the method of the invention includes contacting ablood vessel wall cell in vitro or administering to a subject in vivo,an effective amount of an Aβ40 inhibitor, which has at least one anionicgroup covalently attached to a carrier molecule. As used herein, an“Aβ40 inhibitor” includes compounds which can interfere with the abilityof a CAA-associated Aβ peptide, e.g., Aβ40, to either form fibrils orinteract with a cell surface molecule such as a proteoglycan constituentof a basement membrane, e.g., a glycosaminoglycan. An Aβ40 inhibitor caninterfere with the ability of both fibrillar or non-fibrillarCAA-associated Aβ peptide, e.g., Aβ40, to interact with a cell surfacemolecule.

The Aβ40 inhibitor can have the structure:

Q-[—Y⁻X⁺]_(n)

wherein Y⁻ is an anionic group at physiological pH; Q is a carriergroup; X⁺ is a cationic group; and n is an integer. The number ofanionic groups (“n”) is selected such that the biodistribution of theAβ40 inhibitor for an intended target site is not prevented whilemaintaining activity of the Aβ40 inhibitor. For example, the number ofanionic groups is not so great as to prevent traversal of an anatomicalbarrier, such as a cell membrane, or entry across a physiologicalbarrier, such as the blood-brain barrier. In one embodiment, n is aninteger between 1 and 10. In another embodiment, n is an integer between3 and 8. These compounds are described in U.S. Pat. Nos. 5,643,562,5,972,328, 5,728,375, 5,840,294, and U.S. Application No. 60/131,464.Such compounds also include or can be described as glycosaminoglycan(“GAG”) mimics or mimetics. Other compounds which may be included arethose described in, e.g., Pillot et al., Eur. J. Biochem vol. 243 No. 3,1997 (apoE2, apoE3); WO98/22441; WO98/22430; WO96/10220; WO96/07425; andWO96/39834.

An anionic group of an Aβ40 inhibitor of the invention is a negativelycharged moiety that, when attached to a carrier group, can interferewith the ability of a CAA-associated Aβ peptide, e.g., Aβ40, to eitherform fibrils or interact with a cell surface molecule such as aproteoglycan constituent of a basement membrane, e.g., aglycosaminoglycan (“GAG”). As such, Aβ40 is inhibited from formingdeposits in blood vessels, e.g., cerebral blood vessel wall smoothmuscle cells, thus preventing hardening of the vessel walls and,therefore, cerebral amyloid angiopathy.

For purposes of this invention, the anionic group is negatively chargedat physiological pH. Preferably, the anionic Aβ40 inhibitor mimics thestructure of a sulfated proteoglycan, i.e., is a sulfated compound or afunctional equivalent thereof. “Functional equivalents” of sulfates areintended to include compounds such as sulfamates as well asbioisosteres. Bioisosteres encompass both classical bioisostericequivalents and non-classical bioisosteric equivalents. Classical andnon-classical bioisosteres of sulfate groups are known in the art (seee.g., Silverman, R. B. The Organic Chemistry of Drug Design and DrugAction, Academic Press, Inc.: San Diego, Calif., 1992, pp. 19-23).Accordingly, an Aβ40 inhibitor of the invention can comprise at leastone anionic group including sulfonates, sulfates, sulfamates,phosphonates, phosphates, carboxylates, and heterocyclic groups of thefollowing formulae:

Depending on the carrier group, more than one anionic group can beattached thereto. When more than one anionic group is attached to acarrier group, the multiple anionic groups can be the same structuralgroup (e.g., all sulfonates) or, alternatively, a combination ofdifferent anionic groups can be used (e.g., sulfonates, phosphonates,and sulfates, etc.).

The ability of an Aβ40 inhibitor of the invention to inhibit aninteraction between Aβ40 peptide and a glycoprotein or proteoglycanconstituent of a basement membrane can be assessed by an in vitrobinding assay, such as the one described in Leveugle B. et al. (1998) J.of Neurochem. 70(2):736-744. Briefly, a constituent of the basementmembrane, preferably a glycosaminoglycan (GAG) can be radiolabeled,e.g., at a specific activity of 10,000 cpm, and then incubated with Aβ40peptide-Sepharose beads at, for example, a ratio of 5:1 (v/v) in thepresence or absence of the Aβ40 inhibitor. The Aβ40 peptide-Sepharosebeads and the radiolabeled GAG can be incubated for approximately 30minutes at room temperature and then the beads can be successivelywashed with a Tris buffer solution containing NaCl (0.55 M and 2 M). Thebinding of the basement membrane constituent (e.g., GAG) to the Aβ40peptide can then be measured by collecting the fractions from thewashings and subjecting them to scintillation counting. An Aβ40inhibitor which inhibits an interaction between Aβ40 and a glycoproteinor proteoglycan constituent of a basement membrane, e.g., GAG, willincrease the amount of radioactivity detected in the washings.

In the same manner, the invention relates to a method of diagnosing CAAin vivo, whereas an labeled inhibitor of the invention is administeredto a subject and the disposition of the inhibitor is determined to seewhether a CAA-related condition exists. The label may be oneconventionally known in the art which allows for detection of thecompound either in vivo or in vitro, e.g., radiolabel, fluorescent, etc.Using techniques with which those of ordinary skill in the art will befamiliar, e.g., PET scan, bound tagged inhibitor of the invention may bevisualized, e.g., in regions where CAA would be found, such as near thecerebellum.

Preferably, an Aβ40 inhibitor of the invention interacts with a bindingsite for a basement membrane glycoprotein or proteoglycan in Aβ40 andthereby inhibits the binding of the Aβ40 peptide to the basementmembrane constituent, e.g., GAG. Basement membrane glycoproteins andproteoglycans include GAG, laminin, collagen type IV, fibronectin,chondroitin sulfate, perlecan, and heparan sulfate proteoglycan (HSPG).In a preferred embodiment, the therapeutic compound inhibits aninteraction between an Aβ40 peptide and a GAG. Consensus binding sitemotifs for GAG in amyloidogenic proteins have been described (see, forexample, Hileman R. E. et al. (1998) BioEssays 20:156-167). For example,a GAG consensus binding motif can be of the general formula X—B—B—X—B—Xor X—B—B—B—X—X—B—X, wherein B are basic amino acids (e.g., lysine orarginine) and X are hydropathic amino acids. A GAG consensus bindingmotif can further be of the general formula T-X—X—B—X—X-T-B—X—X—X-T-B—B,wherein T defines a turn of a basic amino acid, Bs are basic amino acids(e.g., lysine, arginine, or occasionally glutamine) and X arehydropathic amino acids. The distance between the first and the secondturn can range from approximately 12 Å to 17 Å. The distance between thesecond and the third turn can be approximately 14 Å. The distancebetween the first and the third turn can range from approximately 13 Åto 18 Å.

Accordingly, in the Aβ40 inhibitors of the invention, when multipleanionic groups are attached to a carrier group, the relative spacing ofthe anionic groups can be chosen such that the anionic groups (e.g.,sulfonates or phosphonates) optimally interact with the basic residueswithin the GAG binding site (thereby inhibiting interaction of GAG withthe site). For example, anionic groups can be spaced approximately15±1.5 Å, 14±1.5 Å and/or 16±1.5 Å apart, or appropriate multiplesthereof, such that the relative spacing of the anionic groups allows foroptimal interaction with a binding site for a basement membraneconstituent (e.g., GAG) in an Aβ40 peptide.

Aβ40 inhibitors of the invention typically further comprise a countercation (i.e., X⁺ in the general formula: Q-[—Y⁻X⁺]_(n)). Cationic groupsinclude positively charged atoms and moieties. If the cationic group ishydrogen, H⁺, then the compound is considered an acid, e.g.,ethanesulfonic acid. If hydrogen is replaced by a metal or itsequivalent, the compound is a salt of the acid. Pharmaceuticallyacceptable salts of the Aβ40 inhibitor are within the scope of theinvention. For example, X⁺ can be a pharmaceutically acceptable alkalimetal, alkaline earth, higher valency cation, polycationic counter ionor ammonium. A preferred pharmaceutically acceptable salt is a sodiumsalt but other salts are also contemplated within their pharmaceuticallyacceptable range.

Within the Aβ40 inhibitor, the anionic group(s) is covalently attachedto a carrier group. Suitable carrier groups include aliphatic groups,alicyclic groups, heterocyclic groups, aromatic groups, and groupsderived from carbohydrates, polymers, peptides, peptide derivatives, orcombinations thereof. A carrier group can be substituted, e.g., with oneor more amino, nitro, halogen, thiol or hydroxyl groups.

As used herein, the term “carbohydrate” is intended to includesubstituted and unsubstituted mono-, oligo-, and polysaccharides.Monosaccharides are simple sugars usually of the formula C₆H₁₂O₆ thatcan be combined to form oligosaccharides or polysaccharides.Monosaccharides include enantiomers and both the D and L stereoisomersof monosaccharides. Carbohydrates can have multiple anionic groupsattached to each monosaccharide moiety. For example, in sucroseoctasulfate, four sulfate groups are attached to each of the twomonosaccharide moieties.

As used herein, the term “polymer” is intended to include moleculesformed by the chemical union of two or more combining subunits calledmonomers. Monomers are molecules or compounds which usually containcarbon and are of relatively low molecular weight and simple structure.A monomer can be converted to a polymer by combination with itself orother similar molecules or compounds. A polymer may be composed of asingle identical repeating subunit or multiple different repeatingsubunits (copolymers). Polymers within the scope of this inventioninclude substituted and unsubstituted vinyl, acryl, styrene andcarbohydrate-derived polymers and copolymers and salts thereof. In oneembodiment, the polymer has a molecular weight of approximately 800-1000Daltons. Examples of polymers with suitable covalently attached anionicgroups (e.g., sulfonates or sulfates) includepoly(2-acrylamido-2-methyl-1-propanesulfonic acid);poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-acrylonitrile);poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-styrene);poly(vinylsulfonic acid); poly(sodium 4-styrenesulfonic acid); andsulfates and/or sulfonates derived from: poly(acrylic acid); poly(methylacrylate); poly(methyl methacrylate); and poly(vinyl alcohol); andpharmaceutically acceptable salts thereof. Examples of polymers withsuitable covalently attached anionic groups include those of theformula:

wherein R is SO₃H or OSO₃H; and pharmaceutically acceptable saltsthereof.

Peptides and peptide derivatives can also act as carriers. The term“peptide” includes two or more amino acids covalently attached through apeptide bond. Amino acids which can be used in peptide carriers includethose naturally occurring amino acids found in proteins such as glycine,alanine, valine, cysteine, leucine, isoleucine, serine, threonine,methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine,arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan.The term “amino acid” further includes analogs, derivatives andcongeners of naturally occurring amino acids, one or more of which canbe present in a peptide derivative. For example, amino acid analogs canhave lengthened or shortened side chains or variant side chains withappropriate functional groups. Also included are the D and Lstereoisomers of an amino acid when the structure of the amino acidadmits of stereoisomeric forms. The term “peptide derivative” furtherincludes compounds which contain molecules which mimic a peptidebackbone but are not amino acids (so-called peptidomimetics), such asbenzodiazepine molecules (see e.g., James, G. L. et al. (1993) Science260:1937-1942). The anionic groups can be attached to a peptide orpeptide derivative through a functional group on the side chain ofcertain amino acids or other suitable functional group. For example, asulfate group can be attached through the hydroxyl side chain of aserine residue. A peptide can be designed to interact with a bindingsite for a basement membrane constituent (e.g., a GAG) in an Aβ40peptide (as described above). Accordingly, in one embodiment, thepeptide comprises four amino acids and anionic groups (e.g., sulfonates)are attached to the first, second and fourth amino acid. For example,the peptide can be Ser-Ser-Y-Ser, wherein an anionic group is attachedto the side chain of each serine residue and Y is any amino acid. Inaddition to peptides and peptide derivatives, single amino acids can beused as carriers in the Aβ40 inhibitor of the invention. For example,cysteic acid, the sulfonate derivative of cysteine, can be used.Peptides such as disclosed in International Application No. WO 00/68263may be used, also, e.g., Lys-Ile-Val-Phe-Phe-Ala (SEQ ID NO:1);Lys-Lys-Leu-Val-Phe-Phe-Ala (SEQ ID NO:2); Lys-Leu-Val-Phe-Phe-Ala (SEQID NO:3); Lys-Phe-Val-Phe-Phe-Ala (SEQ ID NO:4); Ala-Phe-Phe-Val-Leu-Lys(SEQ ID NO:5); Lys-Leu-Val-Phe (SEQ ID NO:6); Lys-Ala-Val-Phe-Phe-Ala(SEQ ID NO:7); Lys-Leu-Val-Phe-Phe (SEQ ID NO:8);Lys-Val-Val-Phe-Phe-Ala (SEQ ID NO:9); Lys-Ile-Val-Phe-Phe-Ala-NH, (SEQID NO:10); Lys-Leu-Val-Phe-Phe-Ala-NH, (SEQ ID NO:11);Lys-Phe-Val-Phe-Phe-Ala-NH, (SEQ ID NO:12); Ala-Phe-Phe-Val-Leu-Lys-NH₂(SEQ ID NO:13); Lys-Leu-Val-Phe-NH₂ (SEQ ID NO:14);Lys-Ala-Val-Phe-Phe-Ala-NH₂ (SEQ ID NO:15); Lys-Leu-Val-Phe-Phe-NH₂ (SEQID NO:16); Lys-Val-Val-Phe-Phe-Ala-NH₂ (SEQ ID NO:17);Lys-Leu-Val-Phe-Phe-Ala-Gln (SEQ ID NO:18);Lys-Leu-Val-Phe-Phe-Ala-Gln-NH₂ (SEQ ID NO:19);His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-NH₂ (SEQ ID NO:20); Asp-Asp-Asp (SEQID NO:21); Lys-Val-Asp-Asp-Gln-Asp (SEQ ID NO:22); His-His-Gln-Lys (SEQID NO:23); and Gln-Lys-Leu-Val-Phe-Phe-NH₂ (SEQ ID NO:24).

The term “aliphatic group” is intended to include organic compoundscharacterized by straight or branched chains, typically having between 1and 22 carbon atoms. Aliphatic groups include alkyl groups, alkenylgroups and alkynyl groups. In complex structures, the chains can bebranched or cross-linked. Alkyl groups include saturated hydrocarbonshaving one or more carbon atoms, including straight-chain alkyl groupsand branched-chain alkyl groups. Such hydrocarbon moieties may besubstituted on one or more carbons with, for example, a halogen, ahydroxyl, a thiol, an amino, an alkoxy, an alkylcarboxy, an alkylthio,or a nitro group. Unless the number of carbons is otherwise specified,“lower aliphatic” as used herein means an aliphatic group, as definedabove (e.g., lower alkyl, lower alkenyl, lower alkynyl), but having fromone to six carbon atoms. Representatives of such lower aliphatic groups,e.g., lower alkyl groups, are methyl, ethyl, n-propyl, isopropyl,2-chloropropyl, n-butyl, sec-butyl, 2-aminobutyl, isobutyl, tert-butyl,3-thiopentyl, and the like. As used herein, the term “amino” means —NH₂;the term “nitro” means —NO₂; the term “halogen” designates —F, —Cl, —Bror —I; the term “thiol” means SH; and the term “hydroxyl” means —OH.Thus, the term “alkylamino” as used herein means —NHR wherein R is analkyl group as defined above. The term “alkylthio” refers to —SR,wherein R is an alkyl group as defined above. The term “alkylcarboxyl”as used herein means —COOR, wherein R is an alkyl group as definedabove. The term “alkoxy” as used herein means —OR, wherein R is an alkylgroup as defined above. Representative alkoxy groups include methoxy,ethoxy, propoxy, tert-butoxy and the like. The terms “alkenyl” and“alkynyl” refer to unsaturated aliphatic groups analogous to alkyls, butwhich contain at least one double or triple bond respectively.

The term “alicyclic group” is intended to include closed ring structuresof three or more carbon atoms. Alicyclic groups include cycloparaffinsor naphthenes which are saturated cyclic hydrocarbons, cycloolefinswhich are unsaturated with two or more double bonds, and cycloacetyleneswhich have a triple bond. They do not include aromatic groups. Examplesof cycloparaffins include cyclopropane, cyclohexane, and cyclopentane.Examples of cycloolefins include cyclopentadiene and cyclooctatetraene.Alicyclic groups also include fused ring structures and substitutedalicyclic groups such as alkyl substituted alicyclic groups. In theinstance of the alicyclics such substituents can further comprise alower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a loweralkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, —CF₃, —CN, orthe like.

The term “heterocyclic group” is intended to include closed ringstructures in which one or more of the atoms in the ring is an elementother than carbon, for example, nitrogen, or oxygen. Heterocyclic groupscan be saturated or unsaturated and heterocyclic groups such as pyrroleand furan can have aromatic character. They include fused ringstructures such as quinoline and isoquinoline. Other examples ofheterocyclic groups include pyridine and purine. Heterocyclic groups canalso be substituted at one or more constituent atoms with, for example,a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a loweralkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, ahydroxyl, —CF₃, —CN, or the like.

The term “aromatic group” is intended to include unsaturated cyclichydrocarbons containing one or more rings. Aromatic groups include 5-and 6-membered single-ring groups which may include from zero to fourheteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazineand pyrimidine, and the like. The aromatic ring may be substituted atone or more ring positions with, for example, a halogen, a lower alkyl,a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino,a lower alkylcarboxyl, a nitro, a hydroxyl, —CF₃, —CN, or the like.

In a preferred embodiment of the method of the invention, the Aβ40inhibitor administered to the subject is comprised of at least onesulfonate group covalently attached to a carrier group, or apharmaceutically acceptable salt thereof. Accordingly, an Aβ40 inhibitorcan have the structure:

Q-[—SO₃ ⁻X⁺]_(n)

wherein Q is a carrier group; X⁺ is a cationic group; and n is aninteger. Suitable carrier groups and cationic groups are those describedhereinbefore. The number of sulfonate groups (“n”) is selected such thatthe biodistribution of the compound for an intended target site is notprevented while maintaining activity of the compound as discussedearlier. In one embodiment, n is an integer between 1 and 10. In anotherembodiment, n is an integer between 3 and 8. As described earlier, anAβ40 inhibitor with multiple sulfonate groups can have the sulfonategroups spaced such that the compound interacts optimally with an HSPGbinding site within the Aβ40 peptide.

In preferred embodiments, the carrier group for a sulfonate(s) is alower aliphatic group (e.g., a lower alkyl, lower alkenyl or loweralkynyl), a heterocyclic group, and group derived from a disaccharide, apolymer or a peptide or peptide derivative. Furthermore, the carrier canbe substituted, e.g., with one or more amino, nitro, halogeno,sulfhydryl or hydroxyl groups. In certain embodiments, the carrier for asulfonate(s) is an aromatic group.

Examples of suitable sulfonated polymeric Aβ40 inhibitors includepoly(2-acrylamido-2-methyl-1-propanesulfonic acid);poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-acrylonitrile);poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-styrene);poly(vinylsulfonic acid); poly(4-styrenesulfonic acid); a sulfonic acidderivative of poly(acrylic acid); a sulfonic acid derivative ofpoly(methyl acrylate); a sulfonic acid derivative of poly(methylmethacrylate); and pharmaceutically acceptable salts thereof.

A preferred sulfonated polymer is poly(vinylsulfonic acid) (PVS) or apharmaceutically acceptable salt thereof, preferably the sodium saltthereof. In one embodiment, PVS having a molecular weight of about800-1000 Daltons is used. PVS may be used as a mixture of isomers or asa single active isomer.

Preferred sulfonated saccharides include5-deoxy-1,2-O-isopropylidene-α-D-xylofuranose-5-sulfonic acid (XXIII,shown as the sodium salt).

Preferred lower aliphatic sulfonated Aβ40 inhibitors for use in theinvention include ethanesulfonic acid; 2-aminoethanesulfonic acid(taurine); cysteic acid (3-sulfoalanine or α-amino-β-sulfopropionicacid); 1-propanesulfonic acid; 1,2-ethanedisulfonic acid;1,3-propanedisulfonic acid; 1,4-butanedisulfonic acid;1,5-pentanedisulfonic acid; and 4-hydroxy-1-butanesulfonic acid (VIII,shown as the sodium salt); and pharmaceutically acceptable saltsthereof. Other aliphatic sulfonated Aβ40 inhibitors contemplated for usein the invention include 1-butanesulfonic acid (XLVII, shown as thesodium salt), 2-propanesulfonic acid (XLIX, shown as the sodium salt),3-pentanesulfonic acid (L, shown as the sodium salt), 4-heptanesulfonicacid (LII, shown as the sodium salt), 1-decanesulfonic acid (XLVIII,shown as the sodium salt); and pharmaceutically acceptable saltsthereof. Sulfonated substituted aliphatic Aβ40 inhibitors contemplatedfor use in the invention include 3-amino-1-propanesulfonic acid (XXII,shown as the sodium salt), 3-hydroxy-1-propanesulfonic acid sulfate(XXXV, shown as the disodium salt), 1,7-dihydroxy-4-heptanesulfonic acid(LIII, shown as the sodium salt); and pharmaceutically acceptable saltsthereof. Yet other sulfonated compounds contemplated for use in theinvention include 2-[(4-pyridinyl)amido]ethanesulfonic acid (LIV,depicted as the sodium salt), and pharmaceutically acceptable saltsthereof.

Preferred heterocyclic sulfonated Aβ40 inhibitors include3-(N-morpholino)-1-propanesulfonic acid; andtetrahydrothiophene-1,1-dioxide-3,4-disulfonic acid; andpharmaceutically acceptable salts thereof.

Aromatic sulfonated Aβ40 inhibitors include 1,3-benzenedisulfonic acid(XXXVI, shown as the disodium salt), 2,5-dimethoxy-1,4-benzenedisulfonicacid (depicted as the disodium salt, XXXVII, or the dipotassium salt,XXXIX), 4-amino-3-hydroxy-1-naphthalenesulfonic acid (XLIII),3,4-diamino-1-naphthalenesulfonic acid (XLIV); and pharmaceuticallyacceptable salts thereof.

In another embodiment of the method of the invention, the Aβ40 inhibitoradministered to the subject is comprised of at least one sulfate groupcovalently attached to a carrier group, or a pharmaceutically acceptablesalt thereof. Accordingly, the Aβ40 inhibitor can have the structure:

Q-[—OSO₃ ⁻X⁺]_(n)

wherein Q is a carrier group; X⁺ is a cationic group; and n is aninteger. Suitable carriers and cationic groups are those describedhereinbefore. The number of sulfate groups (“n”) is selected such thatthe biodistribution of the compound for an intended target site is notprevented while maintaining activity of the Aβ40 inhibitor as discussedearlier. In one embodiment, n is an integer between 1 and 10. In anotherembodiment, n is an integer between 3 and 8. As described earlier, anAβ40 inhibitor with multiple sulfate groups can have the sulfate groupsspaced such that the compound interacts optimally with a GAG bindingsite within an Aβ peptide.

In preferred embodiments, the carrier group for a sulfate(s) is a loweraliphatic group (e.g., a lower alkyl, lower alkenyl or lower alkynyl),an aromatic group, a group derived from a disaccharide, a polymer or apeptide or peptide derivative. Furthermore, the carrier can besubstituted, e.g., with one or more amino, nitro, halogeno, sulfhydrylor hydroxyl groups.

Examples of suitable sulfated polymeric Aβ40 inhibitors includepoly(2-acrylamido-2-methyl-1-propyl sulfuric acid);poly(2-acrylamido-2-methyl-1-propyl sulfuric acid-co-acrylonitrile);poly(2-acrylamido-2-methyl-propyl sulfuric acid-co-styrene);poly(vinylsulfuric acid); poly(sodium 4-styrenesulfate); a sulfatederivative of poly(acrylic acid); a sulfate derivative of poly(methylacrylate); a sulfate derivative of poly(methyl methacrylate); and asulfate derivative of poly(vinyl alcohol); and pharmaceuticallyacceptable salts thereof.

A preferred sulfated polymer is poly(vinylsulfuric acid) orpharmaceutically acceptable salt thereof.

A preferred sulfated disaccharide is sucrose octasulfate orpharmaceutically acceptable salt thereof. Other sulfated saccharidescontemplated for use in the invention include the acid form of methylα-D-glucopyranoside 2,3-disulfate (XVI), methyl4,6-O-benzylidene-α-D-glucopyranoside 2,3-disulfate (XVII),2,3,4,3′,4′-sucrose pentasulfate (XXXIII),1,3:4,6-di-O-benzylidene-D-mannitol 2,5-disulfate (XLI), D-mannitol2,5-disulfate (XLII), 2,5-di-O-benzyl-D-mannitol tetrasulfate (XLV); andpharmaceutically acceptable salts thereof.

Preferred lower aliphatic sulfated Aβ40 inhibitors for use in theinvention include ethyl sulfuric acid; 2-aminoethan-1-ol sulfuric acid;1-propanol sulfuric acid; 1,2-ethanediol disulfuric acid;1,3-propanediol disulfuric acid; 1,4-butanediol disulfuric acid;1,5-pentanediol disulfuric acid; and 1,4-butanediol monosulfuric acid;and pharmaceutically acceptable salts thereof. Other sulfated aliphaticAβ40 inhibitors contemplated for use in the invention include the acidform of 1,3-cyclohexanediol disulfate (XL), 1,3,5-heptanetrioltrisulfate (XIX), 2-hydroxymethyl-1,3-propanediol trisulfate (XX),2-hydroxymethyl-2-methyl-1,3-propanediol trisulfate (XXI),1,3,5,7-heptanetetraol tetrasulfate (XLVI), 1,3,5,7,9-nonanepentasulfate (LI); and pharmaceutically acceptable salts thereof. Othersulfated Aβ40 inhibitors contemplated for use in the invention includethe acid form of 2-amino-2-hydroxymethyl-1,3-propanediol trisulfate(XXIV), 2-benzyloxy-1,3-propanediol disulfate (XXIX),3-hydroxypropylsulfamic acid sulfate (XXX), 2,2′-iminoethanol disulfate(XXXI), N,N-bis(2-hydroxyethyl)sulfamic acid disulfate (XXXII); andpharmaceutically acceptable salts thereof.

Preferred heterocyclic sulfated Aβ40 inhibitors include3-(N-morpholino)-1-propyl sulfuric acid; andtetrahydrothiophene-3,4-diol-1,1-dioxide disulfuric acid; andpharmaceutically acceptable salts thereof.

The invention further contemplates the use of prodrugs which areconverted in vivo to the Aβ40 inhibitors used in the methods of theinvention (see, e.g., R. B. Silverman, 1992, “The Organic Chemistry ofDrug Design and Drug Action”, Academic Press, Chp. 8). Such prodrugs canbe used to alter the biodistribution (e.g., to allow compounds whichwould not typically cross the blood-brain barrier to cross theblood-brain barrier) or the pharmacokinetics of the Aβ40 inhibitor. Forexample, an anionic group, e.g., a sulfate or sulfonate, can beesterified, e.g, with a methyl group or a phenyl group, to yield asulfate or sulfonate ester. When the sulfate or sulfonate ester isadministered to a subject, the ester is cleaved, enzymatically ornon-enzymatically, reductively or hydrolytically, to reveal the anionicgroup. Such an ester can be cyclic, e.g., a cyclic sulfate or sultone,or two or more anionic moieties may be esterified through a linkinggroup. Exemplary cyclic Aβ40 inhibitors include, for example,2-sulfobenzoic acid cyclic anhydride (LV), 1,3-propane sultone (LVI),1,4-butane sultone (LVII), 1,3-butanediol cyclic sulfate (LVIII),α-chloro-α-hydroxy-o-toluenesulfonic acid γ-sultone (LIX), and6-nitronaphth-[1,8-cd]-1,2,-oxathiole 2,2-dioxide (LX). In a preferredembodiment, the prodrug is a cyclic sulfate or sultone. An anionic groupcan be esterified with moieties (e.g., acyloxymethyl esters) which arecleaved to reveal an intermediate Aβ40 inhibitor which subsequentlydecomposes to yield the active Aβ40 inhibitor. In another embodiment,the prodrug is a reduced form of a sulfate or sulfonate, e.g., a thiol,which is oxidized in vivo to the Aβ40 inhibitor. Furthermore, an anionicmoiety can be esterified to a group which is actively transported invivo, or which is selectively taken up by target organs. The ester canbe selected to allow specific targeting of the Aβ40 inhibitors toparticular organs, as described below for carrier moieties.

Carrier groups useful in the Aβ40 inhibitors include groups previouslydescribed, e.g., aliphatic groups, alicyclic groups, heterocyclicgroups, aromatic groups, groups derived from carbohydrates, polymers,peptides, peptide derivatives, or combinations thereof. Suitablepolymers include substituted and unsubstituted vinyl, acryl, styrene andcarbohydrate-derived polymers and copolymers and salts thereof.Preferred carrier groups include a lower alkyl group, a heterocyclicgroup, a group derived from a disaccharide, a polymer, a peptide, orpeptide derivative.

Carrier groups useful in the present invention may also include moietieswhich allow the Aβ40 inhibitor to be selectively delivered to a targetorgan or organs. For example, for a desirable delivery of an Aβ40inhibitor to the brain, the carrier group may include a moiety capableof targeting the Aβ40 inhibitor to the brain, by either active orpassive transport (a “targeting moiety”). Illustratively, the carriergroup may include a redox moiety, as described in, for example, U.S.Pat. Nos. 4,540,564 and 5,389,623, both to Bodor. These patents disclosedrugs linked to dihydropyridine moieties which can enter the brain,where they are oxidized to a charged pyridinium species which is trappedin the brain. Thus, drug accumulates in the brain. Exemplarypyridine/dihydropyridine compounds of the invention include sodium2-(nicotinylamido)-ethanesulfonate (LXII), and1-(3-sulfopropyl)-pyridinium betaine (LXIII). Other carrier moietiesinclude groups, such as those derived from amino acids or thyroxine,which can be passively or actively transported in vivo. An illustrativecompound is phenylalanyltaurine (LXIX), in which a taurine molecule isconjugated to a phenylalanine (a large neutral amino acid). Such acarrier moiety can be metabolically removed in vivo, or can remainintact as part of an active Aβ40 inhibitor. Structural mimics of aminoacids (and other actively transported moieties) are also useful in theinvention (e.g., 1-(aminomethyl)-1-(sulfomethyl)-cyclohexane (LXX)).Other exemplary amino acid mimetics include p-(sulfomethyl)phenylalanine(LXXII), p-(1,3-disulfoprop-2-yl)phenylalanine (LXXIII), andO-(1,3-disulfoprop-2-yl)tyrosine (LXXIV). Exemplary thyroxine mimeticsinclude compounds LXXV, LXVI, and LXXVII. Many targeting moieties areknown, and include, for example, asialoglycoproteins (see, e.g., Wu,U.S. Pat. No. 5,166,320) and other ligands which are transported intocells via receptor-mediated endocytosis (see below for further examplesof targeting moieties which may be covalently or non-covalently bound toa carrier molecule). Furthermore, the Aβ40 inhibitors of the inventionmay bind to amyloidogenic proteins, e.g., Aβ40, in the circulation andthus be transported to the site of action.

The targeting and prodrug strategies described above can be combined toproduce an Aβ40 inhibitor that can be transported as a prodrug to adesired site of action and then unmasked to reveal an active Aβ40inhibitor. For example, the dihydropyridine strategy of Bodor (seesupra) can be combined with a cyclic prodrug, as for example in thecompound 2-(1-methyl-1,4-dihydronicotinoyl)amidomethyl-propanesultone(LXXI).

In one embodiment, the Aβ40 inhibitor in the pharmaceutical compositionsis a sulfonated polymer, for examplepoly(2-acrylamido-2-methyl-1-propanesulfonic acid);poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-acrylonitrile);poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-styrene);poly(vinylsulfonic acid); poly(4-styrenesulfonic acid); a sulfonatederivative of poly(acrylic acid); a sulfonate derivative of poly(methylacrylate); a sulfonate derivative of poly(methyl methacrylate); and asulfonate derivative of poly(vinyl alcohol); and pharmaceuticallyacceptable salts thereof.

In another embodiment, the Aβ40 inhibitor in the pharmaceuticalcompositions is a sulfated polymer, for examplepoly(2-acrylamido-2-methyl-1-propyl sulfuric acid);poly(2-acrylamido-2-methyl-1-propyl sulfuric acid-co-acrylonitrile);poly(2-acrylamido-2-methyl-1-propyl sulfuric acid-co-styrene);poly(vinyl sulfuric acid); poly(4-styrenesulfate); a sulfate derivativeof poly(acrylic acid); a sulfate derivative of poly(methyl acrylate); asulfate derivative of poly(methyl methacrylate); and pharmaceuticallyacceptable salts thereof.

The Aβ40 inhibitor can also have the structure:

wherein Z is XR² or R⁴, R¹ and R² are each independently hydrogen, asubstituted or unsubstituted aliphatic group (preferably a branched orstraight-chain aliphatic moiety having from 1 to 24 carbon atoms in thechain; or an unsubstituted or substituted cyclic aliphatic moiety havingfrom 4 to 7 carbon atoms in the aliphatic ring; preferred aliphatic andcyclic aliphatic groups are alkyl groups, more preferably lower alkyl),an aryl group, a heterocyclic group, or a salt-forming cation; R³ ishydrogen, lower alkyl, aryl, or a salt-forming cation; X is,independently for each occurrence, O or S; R⁴ is hydrogen, lower alkyl,aryl or amino; Y¹ and Y² are each independently hydrogen, halogen (e.g.,F, Cl, Br, or I), lower alkyl, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), hydroxy,alkoxy, or aryloxy; and n is an integer from 0 to 12 (more preferably 0to 6, more preferably 0 or 1). These compounds are described in U.S.Pat. No. 5,869,469, the contents of which is incorporated herein byreference.

Preferred Aβ40 inhibitors for use in the invention include compounds inwhich both R¹ and R² are pharmaceutically acceptable salt-formingcations. It will be appreciated that the stoichiometry of an anioniccompound to a salt-forming counterion (if any) will vary depending onthe charge of the anionic portion of the compound (if any) and thecharge of the counterion. In a particularly preferred embodiment, R¹, R²and R³ are each independently a sodium, potassium or calcium cation. Incertain embodiments in which at least one of R¹ and R² is an aliphaticgroup, the aliphatic group has between 1 and 10 carbons atoms in thestraight or branched chain, and is more preferably a lower alkyl group.In other embodiments in which at least one of R¹ and R² is an aliphaticgroup, the aliphatic group has between 10 and 24 carbons atoms in thestraight or branched chain. In certain preferred embodiments, n is 0 or1; more preferably, n is 0. In certain preferred embodiments of thetherapeutic compounds, Y¹ and Y² are each hydrogen.

In certain preferred embodiments, the Aβ40 inhibitor of the inventioncan have the structure:

in which R¹, R², R³, Y¹, Y², X and n are as defined above. In morepreferred embodiments, the Aβ40 inhibitor of the invention can have thestructure:

wherein R¹, R², R³, Y¹, Y², and X are as defined above, R_(a) and R_(b)are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R_(a)and R_(b), taken together with the nitrogen atom to which they areattached, form a cyclic moiety having from 3 to 8 atoms in the ring, andn is an integer from 0 to 6. In certain preferred embodiments, R_(a) andR_(b) are each hydrogen. In certain preferred embodiments, a compound ofthe invention comprises an α-amino acid (or α-amino acid ester), morepreferably a L-α-amino acid or ester.

The Z, R¹, R², R³, Y¹, Y² and X groups are each independently selectedsuch that the biodistribution of the Aβ40 inhibitor for an intendedtarget site is not prevented while maintaining activity of the Aβ40inhibitor. For example, the number of anionic groups (and the overallcharge on the therapeutic compound) should not be so great as to preventtraversal of an anatomical barrier, such as a cell membrane, or entryacross a physiological barrier, such as the blood-brain barrier, insituations where such properties are desired. For example, it has beenreported that esters of phosphonoformate have biodistribution propertiesdifferent from, and in some cases superior to, the biodistributionproperties of phosphonoformate (see, e.g., U.S. Pat. Nos. 4,386,081 and4,591,583 to Helgstrand et al., and U.S. Pat. Nos. 5,194,654 and5,463,092 to Hostetler et al.). Thus, in certain embodiments, at leastone of R¹ and R² is an aliphatic group (more preferably an alkyl group),in which the aliphatic group has between 10 and 24 carbons atoms in thestraight or branched chain. The number, length, and degree of branchingof the aliphatic chains can be selected to provide a desiredcharacteristic, e.g., lipophilicity. In other embodiments, at least oneof R¹ and R² is an aliphatic group (more preferably an alkyl group), inwhich the aliphatic group has between 1 and 10 carbons atoms in thestraight or branched chain. Again, the number, length, and degree ofbranching of the aliphatic chains can be selected to provide a desiredcharacteristic, e.g., lipophilicity or ease of ester cleavage byenzymes. In certain embodiments, a preferred aliphatic group is an ethylgroup.

In another embodiment, the Aβ40 inhibitor of the invention can have thestructure:

wherein G represents hydrogen or one or more substituents on the arylring (e.g., alkyl, aryl, halogen, amino, and the like) and L is asubstituted alkyl group (in certain embodiments, preferably a loweralkyl), more preferably a hydroxy-substituted alkyl or an alkylsubstituted with a nucleoside base, and M⁺ is a counter ion. In certainembodiments, G is hydrogen or an electron-donating group. In embodimentsin which G is an electron-withdrawing group, G is preferably an electronwithdrawing group at the meta position. The term “electron-withdrawinggroup” is known in the art, and, as used herein, refers to a group whichhas a greater electron-withdrawing than hydrogen. A variety ofelectron-withdrawing groups are known, and include halogens (e.g.,fluoro, chloro, bromo, and iodo groups), nitro, cyano, and the like.Similarly, the term “electron-donating group”, as used herein, refers toa group which is less electron-withdrawing than hydrogen. In embodimentsin which G is an electron donating group, G can be in the ortho, meta orpara position. In certain embodiments, M⁺ is a cationic species selectedfrom, e.g., H⁺ and pharmaceutically acceptable organic or inorganicions, including, without limitation, Na⁺, K⁺, NH₄ ⁺, Ca⁺², RNH₃ ⁺,RR′NH₂ ⁺. In one preferred embodiment, M+ is an anilinium ion.

In certain preferred embodiments, L may be one of the followingmoieties:

Table 1 lists data pertinent to the characterization of these compoundsusing art-recognized techniques. The compounds IVa-IVg in Table 1correspond to the following structure, wherein L is a group selectedfrom the above-listed (Groups IVa-IVg) having the same number.

TABLE 1 COMPOUND ³¹P NMR ¹³C NMR FAB-MS(−) IVa −6.33(DMSO-d₆) 60.97CH₂OH(d, J = 6 Hz) 245.2 66.76 CHOH(d, J = 7.8 Hz) 121.65, 121.78,121.99, 125.71, 129.48, 129.57, 126.43 Aromatic CH 134.38 Aniline C—N150.39 Phenyl C—O(d, J = 7 Hz) 171.57 P—C═O(d, J = 234 Hz) IVb−6.41(DMSO-d₆) 13.94 CH₃ 456 22.11, 24.40, 28.56, 28.72, 28.99, 29.00,31.30, 33.43, —(CH₂)₁₀ ⁻ 65.03 CH₂—OC(O) 66.60 CH₂—OP(d, J = 5.6 Hz)67.71 CH2—OH(d, J = 6 Hz) 121.73, 121.10, 125.64, 126.57, 129.40,129.95, Aromatic CH 134.04 Aniline C—N 150.31 Phenyl C—O 171.44 P—C═O(d,J = 6.7 Hz) 172.83 O—C═O IVc −6.46(DMSO-d₆) 13.94 CH₃ 471 22.11, 25.10,28.68, 28.72, 28.85, 29.00, 30.76, 31.31, 32.10, —(CH₂)₁₀ ⁻ 43.36 CH₂—S68.43 CH₂—OH 68.43 CH—OH(d, J = 6.3 Hz) 68.76 P—O—CH₂-9d, J = 5.8 Hz)121.75, 122.03, 125.62, 126.37, 129.30, 129.53, Aromatic CH 134.23Aniline C—N 150.37 Phenyl C—O(d, J = 6.7 Hz) 171.47 P—C═O(d, J = 234.0Hz) 198.47 S—C═O IVd −6.61(DMSO-d6) 13.94 CH₃ 416 22.06, 25.14, 28.24,28.35, 31.09, 32.14 —CH₂)₆₋ 43.40 CH₂—S 68.50 P—O—CH₂-(d, J = 5.8 Hz)68.77 CH—OH(d, 6.4 Hz) 121.78, 122.59, 125.69, 127.06, 129.43, 129.59Aromatic CH 133.39 Aniline C—N 150.38 Phenyl C—O(d, J = 6.7 Hz) 171.47P—C═O(d, J = 234.4 Hz) 198.54 S—C═O IVe −5.76(D₂O) N/A N/A IVf−7.00(DMSO-d₆) N/A N/A IVg −6.60(DMSO-D6) 70.84 CH2—OH 321 72.17 CH—OH121.68, 121.79, 121.85, 125.71 127.10, 127.92, 129.36, 129.50, 129.59Aromatic CH 134.51 Aniline C—N 142.34 Aromatic C—CH 150.37 Phenyl C—O(d,J = 6.2 Hz) 171.59 P—C═O(d, J = 232.6 Hz)

Note that the structure of some of the Aβ40 inhibitors of this inventionincludes asymmetric carbon atoms. It is to be understood accordinglythat the isomers (e.g., enantiomers and diastereomers) arising from suchasymmetry are included within the scope of this invention. Such isomerscan be obtained in substantially pure form by classical separationtechniques and by sterically controlled synthesis. For the purposes ofthis application, unless expressly noted to the contrary, an Aβ40inhibitor shall be construed to include both the R or S stereoisomers ateach chiral center.

In certain embodiments, an Aβ40 inhibitor of the invention comprises acation (i.e., in certain embodiments, at least one of R¹, R² or R³ is acation). If the cationic group is hydrogen, H⁺, then the Aβ40 inhibitoris considered an acid, e.g., phosphonoformic acid. If hydrogen isreplaced by a metal ion or its equivalent, the Aβ40 inhibitor is a saltof the acid. Pharmaceutically acceptable salts of the Aβ40 inhibitor arewithin the scope of the invention. For example, at least one of R¹, R²or R³ can be a pharmaceutically acceptable alkali metal (e.g., Li, Na,or K), ammonium cation, alkaline earth cation (e.g., Ca²⁺, Ba²⁺, Mg²⁺),higher valency cation, or polycationic counter ion (e.g., a polyammoniumcation). (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J.Pharm. Sci. 66:1-19). It will be appreciated that the stoichiometry ofan anionic compound to a salt-forming counterion (if any) will varydepending on the charge of the anionic portion of the compound (if any)and the charge of the counterion. Preferred pharmaceutically acceptablesalts include a sodium, potassium or calcium salt, but other salts arealso contemplated within their pharmaceutically acceptable range.

The term “pharmaceutically acceptable esters” refers to the relativelynon-toxic, esterified products of the Aβ40 inhibitors of the presentinvention. These esters can be prepared in situ during the finalisolation and purification of the Aβ40 inhibitors or by separatelyreacting the purified Aβ40 inhibitor in its free acid form or hydroxylwith a suitable esterifying agent; either of which are methods known tothose skilled in the art. Carboxylic acids and phosphonic acids can beconverted into esters according to methods well known to one of ordinaryskill in the art, e.g., via treatment with an alcohol in the presence ofa catalyst. A preferred ester group (e.g., when R³ is lower alkyl) is anethyl ester group.

The term “alkyl” refers to the saturated aliphatic groups, includingstraight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl(alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkylsubstituted alkyl groups. In preferred embodiments, a straight chain orbranched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g.,C₁-C₃₀ for straight chain, C₃-C₃₀ for branched chain), and morepreferably 20 or fewer. Likewise, preferred cycloalkyls have from 4-10carbon atoms in their ring structure, and more preferably have 4-7carbon atoms in the ring structure. The term “lower alkyl” refers toalkyl groups having from 1 to 6 carbons in the chain, and to cycloalkylshaving from 3 to 6 carbons in the ring structure.

Moreover, the term “alkyl” (including “lower alkyl”) as used throughoutthe specification and claims is intended to include both “unsubstitutedalkyls” and “substituted alkyls”, the latter of which refers to alkylmoieties having substituents replacing a hydrogen on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It willbe understood by those skilled in the art that the moieties substitutedon the hydrocarbon chain can themselves be substituted, if appropriate.Cycloalkyls can be further substituted, e.g., with the substituentsdescribed above. An “aralkyl” moiety is an alkyl substituted with anaryl (e.g., phenylmethyl (benzyl)).

The term “alkoxy”, as used herein, refers to a moiety having thestructure —O-alkyl, in which the alkyl moiety is described above.

The term “aryl” as used herein includes 5- and 6-membered single-ringaromatic groups that may include from zero to four heteroatoms, forexample, unsubstituted or substituted benzene, pyrrole, furan,thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine,pyrazine, pyridazine and pyrimidine, and the like. Aryl groups alsoinclude polycyclic fused aromatic groups such as naphthyl, quinolyl,indolyl, and the like. The aromatic ring can be substituted at one ormore ring positions with such substituents, e.g., as described above foralkyl groups. Preferred aryl groups include unsubstituted andsubstituted phenyl groups.

The term “aryloxy”, as used herein, refers to a group having thestructure —O-aryl, in which the aryl moiety is as defined above.

The term “amino,” as used herein, refers to an unsubstituted orsubstituted moiety of the formula —NR_(a)R_(b), wherein R_(a) and R_(b)are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R_(a)and R_(b), taken together with the nitrogen atom to which they areattached, form a cyclic moiety having from 3 to 8 atoms in the ring.Thus, the term “amino” is intended to include cyclic amino moieties suchas piperidinyl or pyrrolidinyl groups, unless otherwise stated. An“amino-substituted amino group” refers to an amino group in which atleast one of R_(a) and R_(b), is further substituted with an aminogroup.

In a preferred embodiment, R¹ or R² can be (for at least one occurrence)a long-chain aliphatic moiety. The term “long-chain aliphatic moiety” asused herein, refers to a moiety having a straight or branched chainaliphatic moiety (e.g., an alkyl or alkenyl moiety) having from 10 to 24carbons in the aliphatic chain, e.g., the long-chain aliphatic moiety isan aliphatic chain of a fatty acid (preferably a naturally-occurringfatty acid). Representative long-chain aliphatic moieties include thealiphatic chains of stearic acid, oleic acid, linolenic acid, and thelike.

In certain embodiments, the Aβ40 inhibitor of the invention can have thestructure:

wherein R¹ and R² are each independently hydrogen, an aliphatic group(preferably a branched or straight-chain aliphatic moiety having from 1to 24 carbon atoms, more preferably 10-24 carbon atoms, in the chain; oran unsubstituted or substituted cyclic aliphatic moiety having from 4 to7 carbon atoms in the aliphatic ring), an aryl group, a heterocyclicgroup, or a salt-forming cation; R³ is hydrogen, lower alkyl, aryl, or asalt-forming cation; Y¹ and Y² are each independently hydrogen, halogen(e.g., F, Cl, Br, or I), lower alkyl, hydroxy, alkoxy, or aryloxy; and nis an integer from 0 to 12. Preferred Aβ40 inhibitors for use in theinvention include compounds wherein both R¹ and R² are pharmaceuticallyacceptable salt-forming cations. In a particularly preferred embodiment,R¹, R² and R³ are each independently a sodium, potassium or calciumcation, and n is 0. In certain preferred embodiments of the therapeuticcompounds, Y¹ and Y² are each hydrogen. Particularly preferred Aβ40inhibitors are salts of phosphonoformate. Trisodium phosphonoformate(foscarnet sodium or Foscavir®) is commercially available (e.g., fromAstra), and its clinical pharmacology has been investigated (see, e.g.,“Physician's Desk Reference”, 51st Ed., pp. 541-545 (1997)).

In another embodiment, the Aβ40 inhibitor used in the invention can bean aminophosphonate, a bisphosphonate, a phosphonocarboxylatederivative, a phosphonate derivative, or a phosphono carbohydrate. Forexample, the Aβ40 inhibitor can be one of the compounds describedin—Tables III and IV.

Pharmaceutically Acceptable Formulations

In the methods of the invention, the Aβ40 inhibitor can be administeredin a pharmaceutically acceptable formulation. The present inventionpertains to any pharmaceutically acceptable formulations, such assynthetic or natural polymers in the form of macromolecular complexes,nanocapsules, microspheres, or beads, and lipid-based formulationsincluding oil-in-water emulsions, micelles, mixed micelles, syntheticmembrane vesicles, and resealed erythrocytes.

In one embodiment, the pharmaceutically acceptable formulations comprisea polymeric matrix.

The terms “polymer” or “polymeric” are art-recognized and include astructural framework comprised of repeating monomer units which iscapable of delivering an Aβ40 inhibitor, such that treatment of atargeted condition occurs. The terms also include co-polymers andhomopolymers e.g., synthetic or naturally occurring. Linear polymers,branched polymers, and cross-linked polymers are also meant to beincluded.

For example, polymeric materials suitable for forming thepharmaceutically acceptable formulation employed in the presentinvention, include naturally derived polymers such as albumin, alginate,cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides,as well as synthetic polymers such as polyesters (PLA, PLGA),polyethylene glycol, poloxomers, polyanhydrides, and pluronics. Thesepolymers are biocompatible and biodegradable without producing any toxicbyproducts of degradation, and they possess the ability to modify themanner and duration of Aβ40 inhibitor release by manipulating thepolymer's kinetic characteristics. As used herein, the term“biodegradable” means that the polymer will degrade over time by theaction of enzymes, by hydrolytic action and/or by other similarmechanisms in the body of the subject. As used herein, the term“biocompatible” means that the polymer is compatible with a livingtissue or a living organism by not being toxic or injurious and by notcausing an immunological rejection.

Polymers can be prepared using methods known in the art (Sandier, S. R.;Karo, W. Polymer Syntheses; Harcourt Brace: Boston, 1994; Shalaby, W.;Ikada, Y.; Langer, R.; Williams, J. Polymers of Biological andBiomedical Significance (ACS Symposium Series 540; American ChemicalSociety: Washington, D.C., 1994). Polymers can be designed to beflexible; the distance between the bioactive side-chains and the lengthof a linker between the polymer backbone and the group can becontrolled. Other suitable polymers and methods for their preparationare described in U.S. Pat. Nos. 5,455,044 and 5,576,018.

The polymeric formulations are preferably formed by dispersion of theAβ40 inhibitor within liquefied polymer, as described in U.S. Pat. No.4,883,666, the teachings of which are incorporated herein by reference,or by such methods as bulk polymerization, interfacial polymerization,solution polymerization and ring polymerization as described in OdianG., Principles Of Polymerization And Ring Opening Polymerization, 2nded., John Wiley & Sons, New York, 1981. The properties andcharacteristics of the formulations are controlled by varying suchparameters as the reaction temperature, concentrations of polymer andAβ40 inhibitor, types of solvent used, and reaction times.

In addition to the Aβ40 inhibitor and the pharmaceutically acceptablepolymer, the pharmaceutically acceptable formulation used in the methodof the invention can comprise additional pharmaceutically acceptablecarriers and/or excipients. As used herein, “pharmaceutically acceptablecarrier” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like that are physiologically compatible. For example,the carrier can be suitable for injection into the cerebrospinal fluid.Excipients include pharmaceutically acceptable stabilizers anddisintegrants.

The Aβ40 inhibitor can be encapsulated in one or more pharmaceuticallyacceptable polymers, to form a microcapsule, microsphere, ormicroparticle, terms used herein interchangeably. Microcapsules,microspheres, and microparticles are conventionally free-flowing powdersconsisting of spherical particles of 2 mm or less in diameter, usually500 μm or less in diameter. Particles less than 1 μm are conventionallyreferred to as nanocapsules, nanoparticles or nanospheres. For the mostpart, the difference between a microcapsule and a nanocapsule, amicrosphere and a nanosphere, or microparticle and nanoparticle is size;generally there is little, if any, difference between the internalstructure of the two. In one aspect of the present invention, the meanaverage diameter is less than about 45 μm, preferably less than 20 μm,and more preferably between about 0.1 and 10 μm.

In another embodiment, the pharmaceutically acceptable formulationscomprise lipid-based formulations. Any of the known lipid-based drugdelivery systems can be used in the practice of the invention. Forinstance, multivesicular liposomes (MVL), multilamellar liposomes (alsoknown as multilamellar vesicles or “MLV”), unilamellar liposomes,including small unilamellar liposomes (also known as unilamellarvesicles or “SUV”) and large unilamellar liposomes (also known as largeunilamellar vesicles or “LUV”), can all be used so long as a sustainedrelease rate of the encapsulated Aβ40 inhibitor can be established. Inone embodiment, the lipid-based formulation can be a multivesicularliposome system. Methods of making controlled release multivesicularliposome drug delivery systems is described in PCT Application Nos.US96/11642, US94/12957 and US94/04490.

The composition of the synthetic membrane vesicle is usually acombination of phospholipids, usually in combination with steroids,especially cholesterol. Other phospholipids or other lipids may also beused.

Examples of lipids useful in synthetic membrane vesicle productioninclude phosphatidylglycerols, phosphatidylcholines,phosphatidylserines, phosphatidylethanolamines, sphingolipids,cerebrosides, and gangliosides. Preferably phospholipids including eggphosphatidylcholine, dipalmitoylphosphatidylcholine,distearoylphosphatidylcholine, dioleoylphosphatidylcholine,dipalmitoylphosphatidylglycerol, and dioleoylphosphatidylglycerol areused.

In preparing lipid-based vesicles containing an Aβ40 inhibitor, suchvariables as the efficiency of Aβ40 inhibitor encapsulation, lability ofthe Aβ40 inhibitor, homogeneity and size of the resulting population ofvesicles, Aβ40 inhibitor-to-lipid ratio, permeability, instability ofthe preparation, and pharmaceutical acceptability of the formulationshould be considered (see Szoka, et al., Annual Reviews of Biophysicsand Bioengineering, 9:467, 1980; Deamer, et al., in Liposomes, MarcelDekker, New York, 1983, 27; and Hope, et al., Chem. Phys. Lipids, 40:89,1986, the contents of which are incorporated herein by reference).

Administration of the Pharmaceutically Acceptable Formulation

The Aβ40 inhibitor may be administered to a subject, e.g., parenterally,e.g., intravenously, intradermally, subcutaneously, orally (e.g., viainhalation), transdermally (topically), transmucosally, or rectally. Inone embodiment, the Aβ40 inhibitor is administered by introduction intothe central nervous system of the subject, e.g., into the cerebrospinalfluid of the subject. In certain aspects of the invention, the Aβ40inhibitor is introduced intrathecally, e.g., into a cerebral ventricle,the lumbar area, or the cisterna magna.

The pharmaceutically acceptable formulations can easily be suspended inaqueous vehicles and introduced through conventional hypodermic needlesor using infusion pumps. Prior to introduction, the formulations can besterilized with, preferably, gamma radiation or electron beamsterilization.

In another embodiment of the invention, the Aβ40 inhibitor formulationis administered into a subject intrathecally. As used herein, the term“intrathecal administration” is intended to include delivering an Aβ40inhibitor formulation directly into the cerebrospinal fluid of asubject, by techniques including lateral cerebroventricular injectionthrough a burrhole or cisternal or lumbar puncture or the like(described in Lazorthes et al. Advances in Drug Delivery Systems andApplications in Neurosurgery, 143-192 and Omaya et al., Cancer DrugDelivery, 1: 169-179, the contents of which are incorporated herein byreference). The term “lumbar region” is intended to include the areabetween the third and fourth lumbar (lower back) vertebrae. The term“cisterna magna” is intended to include the area where the skull endsand the spinal cord begins at the back of the head. The term “cerebralventricle” is intended to include the cavities in the brain that arecontinuous with the central canal of the spinal cord. Administration ofan Aβ40 inhibitor to any of the above mentioned sites can be achieved bydirect injection of the Aβ40 inhibitor formulation or by the use ofinfusion pumps. For injection, the Aβ40 inhibitor formulation of theinvention can be formulated in liquid solutions, preferably inphysiologically compatible buffers such as Hank's solution or Ringer'ssolution. In addition, the Aβ40 inhibitor formulation may be formulatedin solid form and re-dissolved or suspended immediately prior to use.Lyophilized forms are also included. The injection can be, for example,in the form of a bolus injection or continuous infusion (e.g., usinginfusion pumps) of the formulation.

Duration and Levels of Administration

In another embodiment of the method of the invention, thepharmaceutically acceptable formulation provides sustained delivery,e.g., “slow release” of the Aβ40 inhibitor to a subject for at leastone, two, three, or four weeks after the pharmaceutically acceptableformulation is administered to the subject.

As used herein, the term “sustained delivery” is intended to includecontinual delivery of an Aβ40 inhibitor in vivo over a period of timefollowing administration, preferably at least several days, a week orseveral weeks. Sustained delivery of the Aβ40 inhibitor can bedemonstrated by, for example, the continued therapeutic effect of theAβ40 inhibitor over time (e.g., sustained delivery of the Aβ40 inhibitorcan be demonstrated by continued inhibition of cerebral amyloidangiopathy over time). Alternatively, sustained delivery of the Aβ40inhibitor may be demonstrated by detecting the presence of the Aβ40inhibitor in vivo over time.

In one embodiment, the pharmaceutically acceptable formulation providessustained delivery of the Aβ40 inhibitor to a subject for less than 30days after the Aβ40 inhibitor is administered to the subject. Forexample, the pharmaceutically acceptable formulation, e.g., “slowrelease” formulation, can provide sustained delivery of the Aβ40inhibitor to a subject for one, two, three or four weeks after the Aβ40inhibitor is administered to the subject. Alternatively, thepharmaceutically acceptable formulation may provide sustained deliveryof the Aβ40 inhibitor to a subject for more than 30 days after the Aβ40inhibitor is administered to the subject.

The pharmaceutical formulation, used in the method of the invention,contains a therapeutically effective amount of the Aβ40 inhibitor. A“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredresult. A therapeutically effective amount of the Aβ40 inhibitor mayvary according to factors such as the disease state, age, and weight ofthe subject, and the ability of the Aβ40 inhibitor (alone or incombination with one or more other agents) to elicit a desired responsein the subject. Dosage regimens may be adjusted to provide the optimumtherapeutic response. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of the Aβ40 inhibitor areoutweighed by the therapeutically beneficial effects. A non-limitingrange for a therapeutically effective concentration of an Aβ40 inhibitoris 100 μM to 1 mM. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of the Aβ40inhibitor and that dosage ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedinvention.

In Vitro Treatment of Blood Vessel Wall Cells

Blood vessel wall cells, or isolated blood vessel wall cells, canfurther be contacted with a therapeutically effective amount of a Aβ40inhibitor, in vitro. Accordingly, such cells can be isolated from asubject and grown in vitro, using techniques well known in the art.Briefly, a smooth muscle cell culture can be obtained by allowing smoothmuscle cells to migrate out of fragments of tissue adhering to asuitable substrate such as a culture dish, or by disaggregating thetissue, e.g., mechanically or enzymatically, to produce a suspension ofcells. For example, the enzymes trypsin, collagenase, elastase,hyaluronidase, DNAse, pronase, dispase, or various combinations thereofcan be used. Trypsin and pronase give the most complete disaggregationbut may damage the cells. Collagenase and dispase give a less completedisaggregation but are less harmful. Methods for isolating tissue suchas neuronal tissue, and the disaggregation of tissue to obtain cellssuch as neuronal cells are described in Freshney R. I., Culture ofAnimal Cells, A Manual of Basic Technique, Third Edition, 1994, thecontents of which are incorporated herein by reference.

Such cells can be subsequently contacted with an Aβ40 inhibitor atlevels and for a duration of time as described above. Once inhibition ofcerebral amyloid angiopathy has been achieved, these neuronal cells canbe re-administered to the subject, e.g., by implantation.

States Characterized by CAA

The present invention further pertains to a method of treating a diseasestate characterized by cerebral amyloid angiopathy in a subject. As usedherein, the term “state” is art recognized and includes a disorder,disease or condition characterized by cerebral amyloid angiopathy.Examples of such disorders include Alzheimer's Disease, HCHWA-D, andhemorrhagic stroke.

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The contents of allreferences, patents and published patent applications cited throughoutthis application are hereby incorporated by reference.

EXAMPLE 1

A compound of the invention is administered in a therapeutic amount to asubject having a clinical diagnosis of ‘probable CAA’, defined forpresent purposes as: multiple hemorrhages confined to the lobar brainregions diagnosed by CT or MRI scan and no other cause of hemorrhage.The ability of the compound of the invention to prevent recurrence ofCAA-related hemorrhages is determined by clinical exams (new neurologicsymptoms or death with acute hemorrhage confirmed by CT scan or autopsy)or by gradient-echo MRI scans which mark the progression of CAA by theappearance of new hemorrhages. The ability of the compound to inhibitthe progression of CAA can also be assessed through cognitive decline(MMSE) or functional decline (NIHSS, FIM). The APOE-2 and APOE-4 areassociated with increasing risk and earlier age of first hemorrhage, butare neither specific nor sensitive for CAA.

EXAMPLE 2

The ability of compounds of the invention to inhibit CAA was measured inthe following example. Nine week old hAPP transgenic mice were treatedfor a period of 8 weeks with two different concentrations of a compoundof the present invention, 3-amino-1-propanesulfonic acid, sodium salt,100 and 30 mg/kg. Mice were administered the compound for 8 weeks, afterwhich they were sacrificed and their brains were perfused and processedfor histological staining with Thioflavin S. This method may also beused as a screening method for determining activity of a candidatecompound for inhibiting CAA.

The extent of CAA in brain sections obtained from these animals wasqualitatively determined following staining. The extent of CAA, if any,was graded as follows:

-   -   + Slight deposition    -   ++ Moderate deposition    -   +++ Severe deposition

The results shown in Table II, below, indicate that the test compoundwas effective in 1) reducing the number of mice showing CAA, and 2)showing an effect on the severity of the deposition seen in the brainvasculature of these animals.

TABLE II # of CAA animals/ # animals animals total CAA SeverityTreatment in study with CAA animals + ++ +++ Vehicle 16 15 15/16 5/159/15 1/15  30 mg/kg 11 10 10/11 6/10 4/10 — 100 mg.kg 15 10 10/15 9/10 —1/10

TABLE III Phosphonoacetic acid

Phosphonoformic acid, trisodium salt hexahydrate

Diethylphosphonoacetic acid

3-[2-(1,2,3,4-Tetrahydroisoquinolinyl)]-1-propanephosphonic acid

3-Aminopropylphosphonic acid NH₂CH₂CH₂CH₂PO₃H₂ Propylphosphonic acidCH₃CH₂CH₂PO₃H₂ Ethylphosphonic acid CH₃CH₂PO₃H₂ Methylphosphonic acidCH₃PO₃H₂ tert-Butylphosphonic acid (CH₃)₃CPO₃H₂ Phenylphosphonic acid

(dl)-2-Amino-3-phosphonopropanoic acid

(1-Aminopropyl)phosphonic acid

(dl)-2-Amino-5-phosphonopentanoic acid

Diethyl phosphoramidate

(S)-2-Amino-2-methyl-4-phosphonobutanoic acid

D-(−)-2-Amino-4-phosphonobutanoic acid

L-(+)-2-Amino-4-phosphonobutanoic acid

D-(−)-2-Amino-7-phosphonoheptanoic acid

L-(+)-2-Amino-7-phosphonoheptanoic acid

D-(−)-2-Amino-6-phosphonohexanoic acid

L-(+)-2-Amino-6-phosphonohexanoic acid

D-(−)-2-Amino-4-phosphonopentanoic acid

L-(+)-2-Amino-4-phosphonopentanoic acid

D-(−)-2-Amino-3-phosphonopropanoic acid

L-(+)-2-Amino-3-phosphonopropanoic acid

3-Aminopropyl(methyl)phosphinic acid, hydrochloride

(R)-(−)-3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (D-CPP)

L-4-[Difluoro(phosphono)methyl)]-phenylalanine

(R,E)-4-(3-Phosphonoprop-2-enyl)piperazine-2-carboxylic acid

trans-L-4-Phosphonomethylproline, trisodium salt

cis-L-4-Phosphonomethylproline, trisodium salt

Thiophosphonoformic acid, trisodium salt

Thiophosphonoacetic acid

Thiophosphonoacetic acid, trisodium salt

Thiophosphonoacetic acid, triethyl ester

Chloro(thiophosphono)acetic acid, trisodium salt

Dichloro(thiophosphono)acetic acid,trisodium salt

Thiophosphonomethylthiophosphonic acid, tetrasodiumsalt

Phenylthiophosphinomethylthio-phosphonic acid,trisodium salt

Propylthiophosphonic acid

Ethylthiophosphonic acid

Methylthiophosphonic acid

tert-Butylthiophosphonic acid

3-Thiophosphonopropanoic acid

Phenylthiophosphonic acid

3-Aminopropylthiophosphonic acid

(dl)-2-Amino-3-thiophosphonopropanoic acid

(1-Aminopropyl)thiophosphonic acid

(dl)-2-Amino-5-thiophosphonopentanoic acid

(S)-2-Amino-2-methyl-4-thiophosphonobutanoic acid

D-2-Amino-4-thiophosphonobutanoic acid

L-2-Amino-4-thiophosphonobutanoic acid

D-2-Amino-7-thiophosphonoheptanoic acid

L-2-Amino-7-thiophosphonoheptanoic acid

D-2-Amino-6-thiophosphonohexanoic acid

L-2-Amino-6-thiophosphonohexanoic acid

D-2-Amino-5-thiophosphonopentanoic acid

L-2-Amino-5-thiophosphonopentanoic acid

D-2-Amino-3-thiophosphonopropanoic acid

L-2-Amino-3-thiophosphonopropanoic acid

3-Aminopropyl(methyl)thiophosphinic acid,hydrochloride

(R)-3-(3-Carboxy-1-piperazinyl)-1-propyl-thiophosphonic acid

L-4-[Difluoro(thiophosphono)methyl)]-phenylalanine

(R,E)-4-(3-Thiophosphonoprop-2-enyl)piperazine-2-carboxylic acid

4-Amino-1-butylphosphonic acid, disodium salt

4-Amino-1-butylthiophosphonic acid, disodium salt

1-(3-Phosphonopropyl)-benzimidazole, disodium salt

1-(3-Thiophosphonopropyl)-benzimidazole, disodiumsalt

3-Dimethylamino-1-propylphosphonic acid, disodiumsalt

N,N-Diethylphosphonoacetamide, disodium salt

N,N-Diethylthiophosphonoacetamide, disodium salt

Diphenylamine-4-phosphonic acid, disodium salt

Diphenylamine-4-thiophosphonic acid, disodium salt

Selenophosphonoformic acid, trisodium salt

Selenophosphonoacetic acid, trisodium salt

D-2-Amino-3-selenophosphonopropanoic acid

L-2-Amino-3-selenophosphonopropanoic acid

D-2-Amino-4-selenophosphonobutanoic acid

L-2-Amino-4-selenophosphonobutanoic acid

N-Cyclohexylphosphonoacetamide, disodium salt

N-Cyclohexylthiophosphonoacetamide, disodium salt

N-Cyclohexylselenophosphonoacetamide, disodium salt

Phosphonoacetic hydrazide, disodium salt

N-Hydroxyphosphonoacetamide, disodium salt

N-Hydroxythiophosphonoacetamide, disodium salt

Thiophosphonoacetic hydrazide, disodium salt

N-Phosphonoacetyl-L-alanine, trisodium salt

N-Thiophosphonoacetyl-L-alanine, trisodium salt

N-Phosphonoacetyl-Glycine, trisodium salt

N-Thiophosphonoacetyl-Glycine, trisodium salt

N-(Phosphonoactyl)-L-asparagine-Glycine, tetrasodiumsalt

N-(Thiophosphonoactyl)-L-asparagine-Glycine,tetrasodium salt

(S)-2-Pyrrolidinemethylthiophosphonic acid, disodiumsalt

(dl)-3-Amino-butylphosphonic acid, disodium salt

(dl)-3-Amino-pentylphosphonic acid, disodium salt

(dl)-3-Amino-hexylphosphonic acid, disodium salt

(dl)-3-Amino-heptylphosphonic acid, disodium salt

(dl)-3-Amino-octylphophonic acid, disodium salt

(dl)-3-Amino-4-methyl-pentylphosphonic acid, disodiumsalt

3-Amino-3-methyl-butylphosphonic acid, disodium salt

(dl)-3-Amino-3-phenyl-propylphosphonic acid,disodium salt

(dl)-3-Amino-4-phenyl-butylphosphonic acid, disodiumsalt

(dl)-3-Amino-4-phenyl-pentylphosphonic acid, disodiumsalt

(dl)-3-Amino-3-phenyl-butylphosphonic acid, disodiumsalt

(dl)-2-Amino-2-(2-phosphonoethyl)-1,2,3,4-tetrahydronaphthalene,disodium salt

1-Amino-1-(2-phosphonoethyl)-cyclohexane, disodiumsalt

(dl)-2-(2-Amino-4-phosphonobutoxy)tetrahydropyran,disodium salt

(dl)-3-Amino-4-hydroxybutylphosphonic acid, disodiumsalt

3-Phosphonopropanesulfonic acid, trisodium salt

Pamidronic acid (3-Amino-1-hydroxypropane-1,1-bisphosphonic acid)

3-Amino-1-hydroxypropane-1,1-bisphosphonic acid,tetrasodium salt

Diethyl 2-pyrrolidinylphosphonate

2-Pyrrolidinylphosphonic acid, disodium salt

1,1-Dioxo-2-(3-phosphonopropyl)-isothiazoline,disodium salt

1,1-Dioxo-2-(3-thiophosphonopropyl)-isothiazolidine,disodium salt

2-Deoxy-2-phosphonoacetylamino-D-glucose

2-Deoxy-2-thiophosphonoacetylamino-D-glucose

1-Amino-3-sulfopropane-1,1-bisphosphonic acid

1-Amino-3-sulfopropane-1,1-bisphosphonic acid,pentasodium salt

3-Hydroxy-3-(2-pyridyl)propenyl-2-phosphonic acid,disodium salt

3-Hydroxy-3-(3-pyridyl)propenyl-2-phosphonic acid,disodium salt

3-Hydroxy-3-(4-pyridyl)propenyl-2-phosphonic acid,disodium salt

3-Amino-3-(2-pyridyl)propenyl-2-phosphonic acid,disodium salt

3-Amino-3-(3-pyridyl)propenyl-2-phosphonic acid,disodium salt

3-Amino-3-(4-pyridyl)propenyl-2-phosphonic acid,disodium salt

1,4-Diamino-1-(3-pyridyl)butyl-2-phosphonic acid,disodium salt

1,4-Diamino-4-methyl-1-(3-pyridyl)pentyl-2-phosphonicacid, disodium salt

1,4-Diamino-4-methyl-1-(2-pyridyl)pentyl-2-phosphonicacid, disodium salt

1,4-Diamino-4-methyl-1-(4-pyridyl)pentyl-2-phosphonicacid, disodium salt

1,3-Diaminopropane-1,1-bisphosphonic acid,tetrasodium salt

1-Amino-3-dimethylaminopropane-1,1-bisphosphonicacid, tetrasodium salt

3-Dimethylamino-1-hydroxypropane-1,1-bisphosphonicacid, tetrasodium salt

1-Hydroxy-3-(methylphenylamino)-propane-1,1-bisphosphonic acid,tetrasodium salt

1-Amino-3-(methylphenylamino)propane-1,1-bisphosphonic acid, tetrasodiumsalt

3-(2-Amino-4,5,7,8-tetrahydro-6H-thiazolo[4,5-d]azepin-6-yl)propyl-phosphonicacid, disodium salt

3-(2-Amino-4,5,7,8-tetrahydro-6H-thiazolo[4,5-d]azepin-6-yl)propyl-thiophosphonicacid, disodium salt

Ibandronic acid, tetrasodium salt(1-Hydroxy-3-(methylpentylamino)-propane-1,1-bisphosphonicacid,tetrasodium salt)

1-Amino-3-(methylpentylamino)propane-1,1-bisphosphonic acid, tetrasodiumsalt

1-Amino-3-(1-benzimidazolyl)propane-1,1-bisphosphonic acid

1-Amino-3-(1-benzimidazolyl)propane-1,1-bisphosphonic acid, tetrasodiumsalt

3-Aminopropane-1,1-bisphosphonic acid, tetrasodiumsalt

(dl)-3-Aminobutane-1,1-bisphosphonic acid,tetrasodium salt

(dl)-3-Aminopentane-1,1-bisphosphonic acid,tetrasodium salt

(dl)-3-Aminohexane-1,1-bisphosphonic acid,tetrasodium salt

(dl)-3-Aminoheptane-1,1-bisphosphonic acid,tetrasodium salt

(dl)-3-Aminooctane-1,1-bisphosphonic acid, tetrasodiumsalt

(dl)-3-Amino-4-methylpentane-1,1-bisphosphonic acid,tetrasodium salt

3-Amino-3-methylbutane-1,1-bisphosphonic acid,tetrasodium salt

(dl)-3-Amino-3-phenylpropane-1,1-bisphosphonic acid,tetrasodium salt

(dl)-3-Amino-4-phenylbutane-1,1-bisphosphonic acid,tetrasodium salt

3-Amino-4-phenylpentane-1,1-bisphosphonic acid,tetrasodium salt

(dl)-3-Amino-3-phenylbutane-1,1-bisphosphonic acid,tetrasodium salt

(dl)-2-(2-Amino-1,2,3,4-tetrahydronaphthalenyl)ethane-1,1-bisphosphonicacid, tetrasodium salt

2-(1-Aminocyclohexyl)ethane-1,1-bisphosphonic acid,tetrasodium salt

2-(2-Amino-4,4-bisphosphonobutoxy)-tetrahydropyran,tetrasodium salt

(dl)-3-Amino-4-hydroxybutane-1,1-bisphosphonic acid,tetrasodium salt

(S)-Hydroxy(2-pyrrolidinyl)methane-bisphosphonicacid, sodium salt

Hydroxy[(2S, 4R)-4-hydroxy-2-pyrrolidinyl]methanebisphosphonic acidtetrasodiumsalt

2-Amino-1-hydroxyethane-1,1-bisphosphonic acid,tetrasodium salt

1,2-Diaminoethane-1,1-bisphonphonic acid, tetrasodiumsalt

4-Amino-1-hydroxybutane-1,1-bisphosphonic acid,sodium salt

1,4-Diaminobutane-1,1-bisphosphonic acid, tetrasodiumsalt

5-Amino-1-hydroxypentane-1,1-bisphosphonic acid,tetrasodium salt

1,5-Diaminopentane-1,1-bisphosphonic acid,tetrasodium salt

(S)-2-Amino-1-hydroxypropane-1,1-bisphosphonic acid,tetrasodium salt

(S)-2-Amino-1-hydroxybutane-1,1-bisphosphonic acid,tetrasodium salt

(S)-2-Amino-1-hydroxy-3-methylbutane-1,1-bisphosphonic acid, tetrasodiumsalt

(S)-2-Amino-1-hydroxy-3-phenylpropane-1,1-bisphosphonic acid,tetrasodium salt

(S)-2-Amino-1,3-dihydroxypropane-1,1-bisphosphonicacid, tetrasodium salt

(S)-2,3-Diamino-1-hydroxypropane-1,1-bisphosphonicacid, tetrasodium salt

(dl)-3-Amino-1-hydroxy-3-phenylpropane-1,1-bisphosphonic acid,tetrasodium salt

(S)-3-Amino-2-(4-chlorophenyl)-1-hydroxypropane-1,1-bisphosphonic acid,tetrasodium salt

(S)-2-Amino-3-(4-aminophenyl)-1-hydroxypropane-1,1-bisphosphonic acid,tetrasodium salt

N-Phosphonomethylglycine

N-Phosphonomethylglycine, trisodium salt

2-Phosphonomethylglutaric acid, tetrasodium salt

2-Phosphonomethylsuccinic acid, tetrasodium salt

(2R,4S)-4-Phosphonomethylpipecolinic acid, trisodiumsalt

(2R,4S)-4-Phosphonomethylpipecolinamide, disodiumsalt

N-Phosphonomethylglycine

N-Phosphonomethylglycine, trisodium salt

3-[6-Methoxy-2-(1,2,3,4-tetrahydro-isoquinolinyl)]propylphosphonic acid,disodium salt

3-[8-Methoxy-2-(1,2,3,4-tetrahydro-isoquinolinyl)]propylphosphonic acid,disodium salt

3-[2-(3-Methoxycarbonyl-1,2,3,4-tetrahydroisoquinolinyl)]-propylphosphonicaciddisodium salt

2-(3-Phosphonopropyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,disodium salt

β-D-Glucopyranosylmethylphosphonic acid, disodiumsalt

α-D-Glucopyranosylmethylphosphonic acid, disodiumsalt

6-Deoxy-6-C-phosphonomethyl-D-glucono-δ-lactone,disodium salt

6-Deoxy-6-C-phosphonomethyl-D-glucose, disodiumsalt

4-Deoxy-4-C-phosphonomethyl-D-glucose, disodiumsalt

3-Deoxy-3-C-phosphonomethyl-D-glucose, disodiumsalt

1-Deoxy-N-phosphonoacetylnojirimycin, disodium salt

(1,5-Dideoxy-1,5-imino-α-D-glucopyranosyl)methylphosphonic acid,disodium salt

1,6-Dideoxy-6-C-phosphonomethyl-nojirimycin,disodium salt

TABLE IV Na⁺⁻O₃SO(CH₂)₃OSO₃ ⁻Na⁺ I II

III

IV

V

VI

VII HOCH₂CH₂CH₂CH₂SO₃ ⁻Na⁺ VIII (Na⁺⁻O₃SCH₂CH₂CH₂CH₂)₂O IX

X

XI

XII XIII

XIV

XV

XVI

XVII XVIII

XIX

XX

XXI

XXII XXIII

XXIV XXV

XXVI

XXVII

XXVIII

XXIX XXX

XXXI

XXXII

XXXIII

XXXIV

XXXV

XXXVI XXXVII

XXXVIII XXXIX

XL

XLI

XLII

XLIII

XLIV

XLV

XLVI CH₃CH₂CH₂CH₂SO₃Na XLVII CH₃(CH₂)₈CH₂SO₃Na XLVIII XLIX

L

LI

LII

LIII

LIV LV

LVI

LVII

LVIII

LIX LX

LXI

LXII

LXIII

LXIV

LXV

LXVI LXVII

LXVIII LXIX

LXX

LXXI LXXII

LXXIII

LXXIV

LXXV

LXXVI LXXVII

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by thefollowing claims. The contents of all references, issued patents, andpublished patent applications cited throughout this application arehereby incorporated by reference. The appropriate components, processes,and methods of those patents, applications and other documents may beselected for the present invention and embodiments thereof.

1. A method of inhibiting cerebral amyloid angiopathy, comprisingcontacting a blood vessel wall cell with an Aβ40 inhibitor, such thatcerebral amyloid angiopathy is inhibited, provided said Aβ40 inhibitoris not 3-amino-1-propanesulfonic acid.
 2. The method of claim 1, whereinthe Aβ40 inhibitor has the following structure:Q-[—Y⁻X⁺]_(n)
 3. The method of claim 1, wherein said Aβ40 inhibitor isselected from the group consisting of ethanesulfonic acid,1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonicacid, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid,2-aminoethanesulfonic acid, 4-hydroxy-1-butanesulfonic acid, andpharmaceutically acceptable salts thereof.
 4. The method of claim 1,wherein said Aβ40 inhibitor is selected from the group consisting of1-butanesulfonic acid, 1-decanesulfonic acid, 2-propanesulfonic acid,3-pentanesulfonic acid, 4-heptanesulfonic acid, and pharmaceuticallyacceptable salts thereof.
 5. The method of claim 1, wherein said Aβ40inhibitor is 1,7-dihydroxy-4-heptanesulfonic acid, or a pharmaceuticallyacceptable salt thereof.
 6. The method of claim 1, wherein said bloodvessel wall cell is selected from the group consisting of blood vesselwall smooth muscle cells, pericytes and endothelial cells.
 7. The methodof claim 1, wherein said blood vessel wall cell is a blood vessel wallsmooth muscle cell.
 8. The method of claim 1, wherein the death of saidblood vessel wall cell is prevented.
 9. The method of claim 1, whereinstructural changes to said blood vessel wall cell are prevented.
 10. Themethod of claim 1, wherein said Aβ40 inhibitor is a peptide or apeptidomimetic which interacts with specific regions of the Aβ peptide.11. The method of claim 1, wherein said Aβ40 inhibitor has the followingstructure:

wherein Z is XR² or R⁴; R¹ and R² are each independently hydrogen, asubstituted or unsubstituted aliphatic group, an aryl group, aheterocyclic group, or a salt-forming cation; R³ is hydrogen, loweralkyl, aryl, or a salt-forming cation; R⁴ is hydrogen, lower alkyl, arylor amino; X is, independently for each occurrence, O or S; Y¹ and Y² areeach independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, oraryloxy; and n is an integer from 0 to
 12. 12. The method of claim 1,wherein said Aβ40 inhibitor is administered in a pharmaceuticallyacceptable formulation.
 13. The method of claim 1, wherein saidpharmaceutically acceptable formulation is a dispersion system.
 14. Themethod of claim 13, wherein said pharmaceutically acceptable formulationcomprises a lipid-based formulation.
 15. The method of claim 14, whereinsaid pharmaceutically acceptable formulation comprises a liposomeformulation.
 16. The method of claim 15, wherein said pharmaceuticallyacceptable formulation comprises a multivesicular liposome formulation.17. The method of claim 12, wherein said pharmaceutically acceptableformulation comprises a polymeric matrix.
 18. The method of claim 17,wherein said polymeric matrix is selected from the group consisting ofnaturally derived polymers, such as albumin, alginate, cellulosederivatives, collagen, fibrin, gelatin, and polysaccharides.
 19. Themethod of claim 17, wherein said polymeric matrix is selected from thegroup consisting of synthetic polymers such as polyesters (PLA, PLGA),polyethylene glycol, poloxomers, polyanhydrides, and pluronics.
 20. Themethod of claim 17, wherein said polymeric matrix is in the form ofmicrospheres.
 21. The method of claim 12, wherein the pharmaceuticallyacceptable formulation provides sustained delivery of said Aβ40inhibitor to a subject.
 22. A method of treating a disease statecharacterized by cerebral amyloid angiopathy in a subject, comprisingadministering an Aβ40 inhibitor to said subject, such that said diseasestate characterized by cerebral amyloid angiopathy is treated, providedsaid Aβ40 inhibitor is not 3-amino-1-propanesulfonic acid.
 23. Themethod of claim 22, wherein said Aβ40 inhibitor has the structure:Q-[—Y⁻X⁺]_(n) wherein Y⁻ is an anionic group at physiological pH; Q is acarrier group; X⁺ is a cationic group; and n is an integer selected suchthat the biodistribution of the Aβ40 inhibitor for an intended targetsite is not prevented while maintaining activity of the Aβ40 inhibitor,such that cerebral amyloid angiopathy is inhibited.
 24. The method ofclaim 22, wherein said Aβ40 inhibitor is selected from the groupconsisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid,1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonicacid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid,4-hydroxy-1-butanesulfonic acid, and pharmaceutically acceptable saltsthereof.
 25. The method of claim 22, wherein said Aβ40 inhibitor isselected from the group consisting of 1-butanesulfonic acid,1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid,4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof.26. The method of claim 22, wherein said Aβ40 inhibitor is1,7-dihydroxy-4-heptane sulfonic acid, or a pharmaceutically acceptablesalt thereof.
 27. The method of claim 22, wherein said blood vessel wallcell is selected from the group consisting of blood vessel wall smoothmuscle cells, pericytes and endothelial cells.
 28. The method of claim22, wherein said blood vessel wall cell is a blood vessel wall smoothmuscle cell.
 29. The method of claim 22, wherein the death of said bloodvessel wall cell is prevented.
 30. The method of claim 22, whereinstructural changes to said blood vessel wall cell are prevented.
 31. Themethod of claim 22, wherein said Aβ40 inhibitor is a peptide or apeptidomimetic which interacts with specific regions of the Aβ peptide.32. The method of claim 22, wherein said Aβ40 inhibitor has thefollowing structure:

wherein Z is XR² or R⁴; R¹ and R² are each independently hydrogen, asubstituted or unsubstituted aliphatic group, an aryl group, aheterocyclic group, or a salt-forming cation; R³ is hydrogen, loweralkyl, aryl, or a salt-forming cation; R⁴ is hydrogen, lower alkyl, arylor amino; X is, independently for each occurrence, O or S; Y¹ and Y² areeach independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, oraryloxy; and n is an integer from 0 to
 12. 33. The method of claim 22,wherein said Aβ40 inhibitor is administered in a pharmaceuticallyacceptable formulation.
 34. The method of claim 33, wherein saidpharmaceutically acceptable formulation is a dispersion system.
 35. Themethod of claim 34, wherein said pharmaceutically acceptable formulationcomprises a lipid-based formulation.
 36. The method of claim 35, whereinsaid pharmaceutically acceptable formulation comprises a liposomeformulation.
 37. The method of claim 36, wherein said pharmaceuticallyacceptable formulation comprises a multivesicular liposome formulation.38. The method of claim 33, wherein said pharmaceutically acceptableformulation comprises a polymeric matrix.
 39. The method of claim 38,wherein said polymeric matrix is selected from the group consisting ofnaturally derived polymers, such as albumin, alginate, cellulosederivatives, collagen, fibrin, gelatin, and polysaccharides.
 40. Themethod of claim 38, wherein said polymeric matrix is selected from thegroup consisting of synthetic polymers such as polyesters (PLA, PLGA),polyethylene glycol, poloxomers, polyanhydrides, and pluronics.
 41. Themethod of claim 38, wherein said polymeric matrix is in the form ofmicrospheres.
 42. The method of claim 33, wherein the pharmaceuticallyacceptable formulation provides sustained delivery of said Aβ40inhibitor to a subject.
 43. A method of inhibiting cerebral amyloidangiopathy in a subject, comprising administering an Aβ40 inhibitor tosaid patient in an effective amount and manner such that said Aβ40inhibitor contacts a blood vessel wall cell in said patient and thatcerebral amyloid angiopathy is inhibited, provided said Aβ40 inhibitoris not 3-amino-1-propanesulfonic acid.
 44. The method of claim 43,wherein the Aβ40 inhibitor has the following structure:Q-[—Y⁻X⁺]_(n) wherein Y⁻ is an anionic group at physiological pH; Q is acarrier group; X⁺ is a cationic group; and n is an integer selected suchthat the biodistribution of the Aβ40 inhibitor for an intended targetsite is not prevented while maintaining activity of the Aβ40 inhibitor,such that cerebral amyloid angiopathy is inhibited.
 45. The method ofclaim 43, wherein said Aβ40 inhibitor is selected from the groupconsisting of ethanesulfonic acid, 1,2-ethanedisulfonic acid,1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonicacid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid,4-hydroxy-1-butanesulfonic acid, and pharmaceutically acceptable saltsthereof.
 46. The method of claim 43, wherein said Aβ40 inhibitor isselected from the group consisting of 1-butanesulfonic acid,1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid,4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof.47. The method of claim 43, wherein said Aβ40 inhibitor is1,7-dihydroxy-4-heptanesulfonic acid, or a pharmaceutically acceptablesalt thereof.
 48. The method of claim 43, wherein said blood vessel wallcell is selected from the group consisting of blood vessel wall smoothmuscle cells, pericytes and endothelial cells.
 49. The method of claim43, wherein said blood vessel wall cell is a blood vessel wall smoothmuscle cell.
 50. The method of claim 43, wherein the death of said bloodvessel wall cell is prevented.
 51. The method of claim 43, whereinstructural changes to said blood vessel wall cell are prevented.
 52. Themethod of claim 43, wherein said Aβ40 inhibitor is a peptide or apeptidomimetic which interacts with specific regions of the Aβ peptide.53. The method of claim 43, wherein said Aβ40 inhibitor has thefollowing structure:

wherein Z is XR² or R⁴; R¹ and R² are each independently hydrogen, asubstituted or unsubstituted aliphatic group, an aryl group, aheterocyclic group, or a salt-forming cation; R³ is hydrogen, loweralkyl, aryl, or a salt-forming cation; R⁴ is hydrogen, lower alkyl, arylor amino; X is, independently for each occurrence, O or S; Y¹ and Y² areeach independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, oraryloxy; and n is an integer from 0 to
 12. 54. The method of claim 43,wherein said Aβ40 inhibitor is administered in a pharmaceuticallyacceptable formulation.
 55. The method of claim 54, wherein saidpharmaceutically acceptable formulation is a dispersion system.
 56. Themethod of claim 55, wherein said pharmaceutically acceptable formulationcomprises a lipid-based formulation.
 57. The method of claim 56, whereinsaid pharmaceutically acceptable formulation comprises a liposomeformulation.
 58. The method of claim 57, wherein said pharmaceuticallyacceptable formulation comprises a multivesicular liposome formulation.59. The method of claim 54, wherein said pharmaceutically acceptableformulation comprises a polymeric matrix.
 60. The method of claim 59,wherein said polymeric matrix is selected from the group consisting ofnaturally derived polymers, such as albumin, alginate, cellulosederivatives, collagen, fibrin, gelatin, and polysaccharides.
 61. Themethod of claim 59, wherein said polymeric matrix is selected from thegroup consisting of synthetic polymers such as polyesters (PLA, PLGA),polyethylene glycol, poloxomers, polyanhydrides, and pluronics.
 62. Themethod of claim 59, wherein said polymeric matrix is in the form ofmicrospheres.
 63. The method of claim 54, wherein the pharmaceuticallyacceptable formulation provides sustained delivery of said Aβ40inhibitor to a subject.
 64. A method of inhibiting cerebral amyloidangiopathy, comprising contacting a blood vessel wall cell with a Aβ40inhibitor having the structure:

wherein Z is XR² or R⁴; R¹ and R² are each independently hydrogen, asubstituted or unsubstituted aliphatic group, an aryl group, aheterocyclic group, or a salt-forming cation; R³ is hydrogen, loweralkyl, aryl, or a salt-forming cation; R⁴ is hydrogen, lower alkyl, arylor amino; X is, independently for each occurrence, O or S; Y¹ and Y² areeach independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, oraryloxy; and n is an integer from 0 to 12, such that cerebral amyloidangiopathy is inhibited.
 65. A method of inhibiting cerebral amyloidangiopathy in a subject, comprising administering an Aβ40 inhibitor tosaid patient in an effective amount and manner such that said Aβ40inhibitor contacts a blood vessel wall cell in said patient, said Aβ40inhibitor having the structure:

wherein Z is XR² or R⁴; R¹ and R² are each independently hydrogen, asubstituted or unsubstituted aliphatic group, an aryl group, aheterocyclic group, or a salt-forming cation; R³ is hydrogen, loweralkyl, aryl, or a salt-forming cation; R⁴ is hydrogen, lower alkyl, arylor amino; X is, independently for each occurrence, O or S; Y¹ and Y² areeach independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, oraryloxy; and n is an integer from 0 to 12, such that cerebral amyloidangiopathy is inhibited.
 66. The method of claim 65, wherein said Aβ40inhibitor has the structure:


67. The method of claim 65, wherein said Aβ40 inhibitor has thestructure:

wherein R^(a) and R^(b) are each independently hydrogen, alkyl, aryl, orheterocyclyl, or R^(a) and R^(b), taken together with the nitrogen atomto which they are attached, form a cyclic moiety having from 3 to 8atoms in the ring, and n is an integer from 0 to
 6. 68. The method ofclaim 67, wherein R^(a) and R^(b) are each hydrogen.
 69. The method ofclaim 65, wherein said Aβ40 inhibitor has the structure:

wherein R¹ and R² are each independently hydrogen, an aliphatic group,an aryl group, a heterocyclic group, or a salt-forming cation; R³ ishydrogen, lower alkyl, aryl, or a salt-forming cation; Y¹ and Y² areeach independently hydrogen, halogen, lower alkyl, hydroxy, alkoxy, oraryloxy; and n is an integer from 0 to
 12. 70. The method of claim 65,wherein R¹ and R² are an aliphatic group selected from the groupconsisting of a branched or straight-chain aliphatic moiety having fromabout 1 to 24 carbon atoms or a branched or straight-chain aliphaticmoiety having from about 10 to 24 carbon atoms, in the chain; and anunsubstituted or substituted cyclic aliphatic moiety having from 4 to 7carbon atoms in the aliphatic ring.
 71. A method of inhibiting cerebralamyloid angiopathy in a subject, comprising administering an Aβ40inhibitor to said patient in an effective amount and manner such thatsaid Aβ40 inhibitor contacts a blood vessel wall cell in said patient,said Aβ40 inhibitor having the structure:

wherein G represents hydrogen or one or more substituents on the arylring and L is a substituted alkyl group, and M⁺ is a counter ion, suchthat cerebral amyloid angiopathy is inhibited.
 72. The method of claim71, where G is hydrogen or an electron-donating group.
 73. The method ofclaim 71, where G is an electron-withdrawing group at the meta position.